Anti-respiratory syncytial virus antibodies, and methods of their generation and use

ABSTRACT

Anti-RSV antibodies with neutralizing potency against RSV subtype A and RSV subtype B are provided, as well as methods for their identification, isolation, generation, and methods for their preparation and use are provided.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. application Ser. No.16/343,311, filed Apr. 18, 2019, which is a 371(c) U.S. Nat'l Phaseapplication of Int'l Appl. No. PCT/US2017/057737, filed Oct. 20, 2017,which claims the benefit of U.S. Provisional Patent Application No.62/411,508, filed Oct. 21, 2016, the entire contents of which areincorporated herein by reference.

SEQUENCE LISTING

The contents of the electronic sequence listing (1160430o004202.xml;Size: 3,081,456 bytes; and Date of Creation: Oct. 31, 2022) is hereinincorporated by reference in its entirety.

FIELD OF THE INVENTION

The invention relates, inter alia, to anti-Respiratory Syncytial Virus(RSV) antibodies and functional fragments thereof, and methods andreagents for their preparation and use.

BACKGROUND OF THE INVENTION

All references cited herein, including without limitation patents,patent applications, and non-patent references and publicationsreferenced throughout are hereby expressly incorporated by reference intheir entireties for all purposes.

Respiratory syncytial virus (RSV) causes substantial morbidity andmortality in young children and the elderly, is the leading cause ofinfant hospitalization in the United States and accounts for anestimated 64 million infections and 160,000 deaths world-wide each year.However, despite decades of research, the development of a safe andeffective vaccines or therapeutic and/or prophylactic antibodies againstRSV has remained elusive, highlighting the need for novel strategiesthat induce or provide protective immune responses. (1-3). Indeed, todate there are currently no approved RSV vaccines, and passiveprophylaxis with the monoclonal antibody palivizumab (marketed asSynagis®) is restricted to high-risk infants in part due to its modestefficacy.

Certain populations of children are at risk for developing an RSVinfection and these include preterm infants (Hall et al., 1979, NewEngl. J. Med. 300:393-396), children with congenital malformations ofthe airway, children with bronchopulmonary dysplasia (Groothuis et al.,1988, Pediatrics 82:199-203), children with congenital heart disease(MacDonald et al., New Engl. J. Med. 307:397-400), and children withcongenital or acquired immunodeficiency (Ogra et al., 1988, Pediatr.Infect. Dis. J. 7:246-249; and Pohl et al., 1992, J. Infect. Dis.165:166-169), and cystic fibrosis (Abman et al., 1988, J. Pediatr. 113:826-830).

RSV can infect the adult population as well. In this population, RSVcauses primarily an upper respiratory tract disease, although elderlypatients may be at greater risk for a serious infection and pneumonia(Evans, A. S., eds., 1989, Viral Infections of Humans. Epidemiology andControl, 3^(rd) ed., Plenum Medical Book, New York at pages 525-544), aswell as adults who are immunosuppressed, particularly bone marrowtransplant patients (Hertz et al., 1989, Medicine 68:269-281). Other atrisk patients include those suffering from congestive heart failure andthose suffering from chronic obstructive pulmonary disease (ie. COPD).There have also been reports of epidemics among nursing home patientsand institutionalized young adults (Falsey, A. R., 1991, Infect. ControlHosp. Epidemiol. 12:602-608; and Garvie et al., 1980, Br. Med. J.281:1253-1254).

While treatment options for established RSV disease are limited, moresevere forms of the disease of the lower respiratory tract often requireconsiderable supportive care, including administration of humidifiedoxygen and respiratory assistance (Fields et al., eds, 1990, FieldsVirology, 2^(nd) ed., Vol. 1, Raven Press, New York at pages 1045-1072).

Similar to other pneumoviruses, RSV expresses two major surfaceglycoproteins: the fusion protein (F) and the attachment protein (G).Although both have been shown to induce protective neutralizing antibodyresponses, F is less genetically variable than G, is absolutely requiredfor infection, and is the target for the majority of neutralizingactivity in human serum (4-8). RSV F is also the target of themonoclonal antibody palivizumab, which is used to passively protecthigh-risk infants from severe disease (9). Consequently, the RSV Fprotein is considered to be a highly attractive target for vaccines andantibody-based therapies.

The mature RSV F glycoprotein initially exists in a metastable prefusionconformation (10), before undergoing a conformational change that leadsto insertion of the hydrophobic fusion peptide into the host-cellmembrane. Subsequent refolding of F into a stable, elongated postfusionconformation (postF) (11, 12) results in fusion of the viral andhost-cell membranes. Due to its inherent instability, the preF proteinhas the propensity to prematurely trigger into postF, both in solutionand on the viral surface (13). Recently, stabilization of preF has beenachieved by protein engineering (14, 15), and stabilized preF has beenshown to induce higher titers of neutralizing antibodies than postF inanimal models (15).

Despite the importance of neutralizing antibodies in protection againstsevere RSV disease, our understanding of the human antibody response toRSV has been limited to studies of human sera and a small number ofRSV-specific human monoclonal antibodies (16-19). The epitopesrecognized by these human antibodies, as well as several murineantibodies, have defined at least four ‘antigenic sites’ on RSV F (1,10, 16, 18-20) (see also, e.g, Table 1). Three of these sites—I, II, andIV—are present on both pre- and postF, whereas antigenic site Ø existsexclusively on preF. Additional preF-specific epitopes have been definedby antibodies MPE8 (17) and AM14 (21). Although serum mapping studieshave shown that site 0-directed antibodies are responsible for a largeproportion of the neutralizing antibody response in most individuals(8), there are additional antibody specificities that contribute toserum neutralizing activity that remain to be defined. In addition, itwas heretofore unknown whether certain antibody sequence features arerequired for recognition of certain neutralizing sites, as observed forother viral targets (22-25). Accordingly, understanding the relationshipbetween neutralization potency and epitope specificity would beadvantageous in the selection and/or design of vaccine antigens, as wellas therapeutic and/or prophylactic antibodies, which induce potentneutralizing responses to RSV.

While treatment options for established RSV disease are limited, moresevere forms of the disease of the lower respiratory tract often requireconsiderable supportive care, including administration of humidifiedoxygen and respiratory assistance (Fields et al., eds, 1990, FieldsVirology, 2^(nd) ed., Vol. 1, Raven Press, New York at pages 1045-1072).

Ribavirin, which is the only drug approved for treatment of infection,has been shown to be effective in the treatment of pneumonia andbronchiolitis associated with RSV infection, and has been shown tomodify the course of severe RSV disease in immunocompetent children(Smith et ai., 1991, New Engl. J. Med. 325:24-29). The use of ribavirinis limited due to concerns surrounding its potential risk to pregnantwomen who may be exposed to the aerosolized drug while it is beingadministered in a hospital environment.

Similarly, while a vaccine may be useful, no commercially availablevaccine has been developed to date. Several vaccine candidates have beenabandoned and others are under development (Murphy et al., 1994, VirusRes. 32: 13-36). The development of a vaccine has proven to beproblematic. In particular, immunization would be required in theimmediate neonatal period since the peak incidence of lower respiratorytract disease occurs at 2-5 months of age. However, it is known that theneonatal immune response is immature at that time. Plus, the infant atthat point in time still has high titers of maternally acquired RSVantibody, which might reduce vaccine immunogenicity (Murphy et al.,1988, J. Virol. 62:3907-3910; and Murphy et ai, 1991, Vaccine9:185-189).

Currently, the only approved approach to prophylaxis of RSV disease ispassive immunization. For example, the humanized antibody, palivizumab(SYNAGIS®), which is specific for an epitope on the F protein, isapproved for intramuscular administration to pediatric patients forprevention of serious lower respiratory tract disease caused by RSV atrecommended monthly doses of 15 mg/kg of body weight throughout the RSVseason (November through April in the northern hemisphere). SYNAGIS® isa composite of human (95%) and murine (5%) antibody sequences. (Johnsonet ai, (1997), J. Infect. Diseases 176:1215-1224 and U.S. Pat. No.5,824,307).

Although SYNAGIS® has been successfully used for the prevention of RSVinfection in pediatric patients, multiple intramuscular doses of 15mg/kg of SYNAGIS® are required to achieve a prophylactic effect. Thenecessity for the administration of multiple intramuscular doses ofantibody requires repeated visits to the doctor's office, which is notonly inconvenient for the patient but can also result in missed doses.

Efforts were made to improve on the therapeutic profile of an anti-RSV-Fantibody, and this lead to the identification and development ofmotavizumab, also referred to as NUMAX™ However, clinical testingrevealed that certain of the patients being administered motavizumabwere having severe hypersensitivity reactions. Further development ofthis humanized anti-RSV-F antibody was then discontinued.

Other antibodies to RSV-F protein have been described and can be foundin U.S. Pat. Nos. 6,656,467; 5,824,307, 7,786,273; 7,670,600; 7,083,784;6,818,216; 7,700,735; 7,553,489; 7,323,172; 7,229,619; 7,425,618;7,740,851; 7,658,921; 7,704,505; 7,635,568; 6,855,493; 6,565,849;7,582,297; 7,208,162; 7,700,720; 6,413,771; 5,811,524; 6,537,809;5,762,905; 7,070,786; 7,364,742; 7,879,329; 7,488,477; 7,867,497;5,534,411; 6,835,372; 7,482,024; 7,691,603; 8,562,996; 8,568,726;US20100015596; WO2009088159A1; and WO2014159822. To date, none otherthan SYNAGIS® has been approved by a regulatory agency for use inpreventing an RSV infection.

There remains a need for the provision of highly specific, highaffinity, and highly potent neutralizing anti-RSV antibodies andantigen-binding fragments thereof with neutralize at least one, butpreferably both, of subtype A and subtype B RSV viral strains, and whichpreferentially recognize PreF relative to Post F conformations of the Fprotein. There also remains a need for the provision of anti-RSV andanti-HMPV cross-neutralizing antibodies and antigen-binding fragmentsthereof.

SUMMARY OF THE INVENTION

Applicants have now discovered, isolated, and characterized, inter alia,an extensive panel of RSV F-specific monoclonal antibodies from thememory B cells of a healthy adult human donor and used these antibodiesto comprehensively map the antigenic topology of RSV F. A largeproportion of the RSV F-specific human antibody repertoire wasadvantageously comprised of antibodies with greatly enhanced specificityfor the PreF conformation of the F protein (relative to the PostF form),many if not most of which exhibited remarkable potency in neutralizationassays against one or both of RSV subtype A and RSV subtype B strains.Indeed, a large number of these antibodies display neutralizationpotencies that are multiple-fold greater—some 5- to 100-fold greater ormore—to previous anti-RSV therapeutic antibodies, such as D25 andpavlizumamab thus serve as attractive therapeutic and/or prophylacticcandidates for treating and/or preventing RSV infection and disease.

The most potent antibodies were found to target two distinct antigenicsites that are located near the apex of the preF trimer, providingstrong support for the development of therapeutic and/or prophylacticantibodies targeting these antigenic sites, as well as preF-basedvaccine candidates that preserve these antigenic sites. Furthermore, theneutralizing antibodies described and disclosed herein represent newopportunities for the prevention of severe RSV disease using passiveimmunoprophylaxis.

Given the role that the F protein plays in fusion of the virus with thecell and in cell to cell transmission of the virus, the antibodiesdescribed herein provide a method of inhibiting that process and assuch, may be used for preventing infection of a patient exposed to, orat risk for acquiring an infection with RSV, or for treating and/orameliorating one or more symptoms associated with RSV infection in apatient exposed to, or at risk for acquiring an infection with RSV, orsuffering from infection with RSV. The antibodies described herein mayalso be used to prevent or to treat an RSV infection in a patient whomay experience a more severe form of the RSV infection due to anunderlying or pre-existing medical condition. A patient who may benefitfrom treatment with an antibody of the invention may be a pre-terminfant, a full-term infant born during RSV season (approximately latefall (November) through early spring (April)) that is at risk because ofother pre-existing or underlying medical conditions including congenitalheart disease or chronic lung disease, a child greater than one year ofage with or without an underlying medical condition, aninstitutionalized or hospitalized patient, or an elderly adult (>65years of age) with or without an underlying medical condition, such ascongestive heart failure (CHF), or chronic obstructive pulmonary disease(COPD). A patient who may benefit from such therapy may suffer from amedical condition resulting from a compromised pulmonary,cardiovascular, neuromuscular, or immune system. For example, thepatient may suffer from an abnormality of the airway, or an airwaymalfunction, a chronic lung disease, a chronic or congenital heartdisease, a neuromuscular disease that compromises the handling ofrespiratory secretions, or the patient may be immunosuppressed due tosevere combined immunodeficiency disease or severe acquiredimmunodeficiency disease, or from any other underlying infectiousdisease or cancerous condition that results in immunosuppression, or thepatient may be immunosuppressed due to treatment with animmunosuppressive drug (e.g. any drug used for treating a transplantpatient) or radiation therapy. A patient who may benefit from theantibodies of the invention may be a patient that suffers from chronicobstructive pulmonary disease (COPD), cystic fibrosis (CF),bronchopulmonary dysplasia, congestive heart failure (CHF), orcongenital heart disease.

Because the inventive antibodies and antigen-binding fragments thereofare more effective at neutralization of RSV compared to knownantibodies, lower doses of the antibodies or antibody fragments could beused to achieve a greater level of protection against infection withRSV, and more effective treatment and/or amelioration of symptomsassociated with an RSV infection. Accordingly, the use of lower doses ofantibodies or fragments thereof which immunospecifically bind to RSV-Fantigen may result in fewer or less severe adverse events. Likewise, theuse of more effective neutralizing antibodies may result in a diminishedneed for frequent administration of the antibodies or antibody fragmentsthan previously envisioned as necessary for the prevention of infection,or for virus neutralization, or for treatment or amelioration of one ormore symptoms associated with an RSV infection. Symptoms of RSVinfection may include a bluish skin color due to lack of oxygen(hypoxia), breathing difficulty (rapid breathing or shortness ofbreath), cough, croupy cough (“seal bark” cough), fever, nasal flaring,nasal congestion (stuffy nose), apnea, decreased appetite, dehydration,poor feeding, altered mental status, or wheezing.

Such antibodies may be useful when administered prophylactically (priorto exposure to the virus and infection with the virus) to lessen theseverity, or duration of a primary infection with RSV, or ameliorate atleast one symptom associated with the infection. The antibodies may beused alone or in conjunction with a second agent useful for treating anRSV infection. In certain embodiments, the antibodies may be giventherapeutically (after exposure to and infection with the virus) eitheralone, or in conjunction with a second agent to lessen the severity orduration of the primary infection, or to ameliorate at least one symptomassociated with the infection. In certain embodiments, the antibodiesmay be used prophylactically as stand-alone therapy to protect patientswho are at risk for acquiring an infection with RSV, such as thosedescribed above. Any of these patient populations may benefit fromtreatment with the antibodies of the invention, when given alone or inconjunction with a second agent, including for example, an anti-viraltherapy, such as ribavirin, or other anti-viral vaccines.

The antibodies of the invention can be full-length (for example, an lgG1or lgG4 antibody) or may comprise only an antigen-binding portion (forexample, a Fab, F(ab′)₂ or scFv fragment), and may be modified to affectfunctionality, e.g., to eliminate residual effector functions (Reddy etal., (2000), J. Immunol. 164:1925-1933).

Accordingly, in certain embodiments are provided isolated antibodies orantigen-binding fragments thereof that specifically bind to RespiratorySyncytial Virus (RSV) F protein (F), wherein at least one of the CDRH1,a CDRH2, a CDRH3, a CDRL1, a CDRL2, and CDRL3 amino acid sequence suchantibodies or the antigen-binding fragments thereof are at least 70%identical; at least 75% identical; 80% identical; at least 85%identical; at least 90% identical; at least 95% identical; at least 96%identical; at least 97% identical; at least 98% identical; at least 99%;and/or all percentages of identity in between; to at least one theCDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acidsequences as disclosed in Table 6 of an antibody selected from AntibodyNumber 232 through Antibody Number 372 as disclosed in Table 6; andwherein said antibody or the antigen-binding fragment thereof also hasone or more of the following characteristics: a) the antibodies orantigen-binding fragments thereof cross-compete with said antibodies orantigen-binding fragments thereof for binding to RSV-F; b) theantibodies or antigen-binding fragments thereof display better bindingaffinity for the PreF form of RSV-F relative to the PostF form; c) theantibodies or antigen-binding fragments thereof display a clean or lowpolyreactivity profile; d) the antibodies or antigen-binding fragmentsthereof display neutralization activity toward RSV subtype A and RSVsubtype B in vitro; e) the antibodies or antigen-binding fragmentsthereof display antigenic site specificity for RSV-F at Site Ø, Site I,Site II, Site III, Site IV, or Site V f) the antibodies orantigen-binding fragments thereof display antigenic site specificity forRSV-F Site Ø, Site V, or Site III relative to RSV-F Site I, Site II, orSite IV; g) at least a portion of the epitope with which the antibodiesor antigen-binding fragments thereof interact comprises the α3 helix andβ3/β4 hairpin of PreF; h) the antibodies or antigen-binding fragmentsthereof display an in vitro neutralization potency (IC₅₀) of betweenabout 0.5 microgram/milliliter (ug/ml) to about 5 ug/ml; between about0.05 ug/ml to about 0.5 ug/ml; or less than about 0.05 mg/ml; i) thebinding affinities and/or epitopic specificities of the antibodies orantigen-binding fragments thereof for any one of the RSV-F variantsdesignated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced oreliminated relative to the binding affinities and/or epitopicspecificities of said antibodies or antigen-binding fragments thereoffor the RSV-F or RSV-F DS-Cav1; j) the antibodies or antigen-bindingfragments thereof display a cross-neutralization potency (IC₅₀) againsthuman metapneumovirus (HMPV); k) the antibodies or antigen-bindingfragments thereof do not complete with D25, MPE8, palivizumab, ormotavizumab; or 1) the antibodies or antigen-binding fragments thereofdisplay at least about 2-fold; at least about 3-fold; at least about4-fold; at least about 5-fold; at least about 6-fold; at least about7-fold; at least about 8-fold; at least about 9-fold; at least about10-fold; at least about 15-fold; at least about 20-fold; at least about25-fold; at least about 30-fold; at least about 35-fold; at least about40-fold; at least about 50-fold; at least about 55-fold; at least about60-fold; at least about 70-fold; at least about 80-fold; at least about90-fold; at least about 100-fold; greater than about 100-fold; and foldsin between any of the foregoing; greater neutralization potency (IC50)than D25 and/or palivizumab.

In certain other embodiments, the isolated antibodies or antigen-bindingfragments thereof comprise: at least two; at least three; at least 4; atleast 5; at least 6; at least 7; at least 8; at least 9; at least 10; atleast 11; or at least 12; of characteristics a) through 1) above.

In certain other embodiments, the isolated antibodies or antigen-bindingfragments thereof comprise: a) the CDRH3 amino acid sequence of any oneof the antibodies designated Antibody Number 232 through Antibody Number372 as disclosed in Table 6; b) the CDRH2 amino acid sequence of any oneof the antibodies designated Antibody Number 232 through Antibody Number372 as disclosed in Table 6; c) the CDRH1 amino acid sequence of any oneof the antibodies designated Antibody Number 232 through Antibody Number372 as disclosed in Table 6; d) the CDRL3 amino acid sequence of any oneof the antibodies designated Antibody Number 232 through Antibody Number372 as disclosed in Table 6; e) the CDRL2 amino acid sequence of any oneof the antibodies designated Antibody Number 232 through Antibody Number372a s disclosed in Table 6; f) the CDRL1 amino acid sequence of any oneof the antibodies designated Antibody Number 232 through Antibody Number372 as disclosed in Table 6; or g) any combination of two or more of a),b), c), d), e), and f).

In certain other embodiments, the isolated antibodies or antigen-bindingfragments thereof comprise: a) a heavy chain (HC) amino acid sequence ofany one of the antibodies designated Antibody Number 232 throughAntibody Number 372 as disclosed in Table 6; and/or b) a light chain(LC) amino acid sequence of any one of the antibodies designatedAntibody Number 232 through Antibody Number 372 as disclosed in Table 6.

In certain other embodiments, the isolated antibodies or antigen-bindingfragments thereof are selected from the group consisting of antibodiesthat are at least 70% identical; at least 75% identical; 80% identical;at least 85% identical; at least 90% identical; at least 95% identical;at least 96% identical; at least 97% identical; at least 98% identical;at least 99%; and/or all percentages of identity in between; to any oneof the antibodies designated as Antibody Number 232 through AntibodyNumber 372 as disclosed in Table 6.

In certain other embodiments, the isolated antibodies or antigen-bindingfragments thereof are selected from the group consisting of theantibodies designated as Antibody Number 232 through Antibody Number 372as disclosed in Table 6.

In other embodiments are provided isolated nucleic acid sequencesencoding antibodies or antigen-binding fragments thereof according toany of the other embodiments disclosed herein.

In other embodiments are provided expression vectors comprising isolatednucleic acid sequences according to other embodiments disclosed herein.

In other embodiments are provided host cells transfected, transformed,or transduced with nucleic acid sequences or expression vectorsaccording to other embodiments disclosed herein.

In other embodiments are provided pharmaceutical compositionscomprising: one or more of the isolated antibodies or antigen-bindingfragments thereof according to other embodiments disclosed herein; and apharmaceutically acceptable carrier and/or excipient.

In other embodiments are provided pharmaceutical compositions: one ormore nucleic acid sequences according other embodiments disclosedherein; or one or more the expression vectors according to otherembodiments disclosed herein; and a pharmaceutically acceptable carrierand/or excipient.

In other embodiments are provided transgenic organisms comprisingnucleic acid sequences according to other embodiments disclosed herein;or expression vectors according to other embodiments disclosed herein.

In other embodiments are provided methods of treating or preventing aRespiratory Syncytial Virus (RSV) infection, ar at least one symptomassociated with RSV infection, comprising administering to a patient inneed there of or suspected of being in need thereof: a) one or moreantibodies or antigen-binding fragments thereof according to otherembodiments disclosed herein; b) nucleic acid sequences according toother embodiments disclosed herein; an expression vector according toother embodiments disclosed herein; a host cell according to otherembodiments disclosed herein; or e) a pharmaceutical compositionaccording to other embodiments disclosed herein; such that the RSVinfection is treated or prevented, or the at least on symptom associatedwith RSV infection is treated, alleviated, or reduced in severity.

In other embodiments are provided methods of treating or preventingeither a Respiratory Syncytial Virus (RSV) infection or a humanmetapneumovirus (HMPV) infection, ar at least one symptom associatedwith said RSV infection or said HMPV infection, comprising administeringto a patient in need thereof or suspected of being in need thereof: a)one or more antibodies or antigen-binding fragments thereof according toother embodiments disclosed herein; b) a nucleic acid sequencesaccording to other embodiments disclosed herein; c) an expression vectoraccording to other embodiments disclosed herein; d) a host cellaccording to other embodiments disclosed herein; or e) a pharmaceuticalcomposition according to other embodiments disclosed herein; such thatthe RSV infection is treated or prevented, or the at least on symptomassociated with RSV infection is treated, alleviated, or reduced inseverity. In other embodiments are provided methods according to otherembodiments wherein the one or more antibodies or antigen-bindingfragments thereof of a) is selected from the group consisting of theantibodies designated as Antibody Number 340 as disclosed in Table 6.

In other embodiments are provided methods according to other embodimentswherein the method further comprises administering to the patient asecond therapeutic agent.

In other embodiments are provided methods according to otherembodiments, wherein the second therapeutic agent is selected groupconsisting of: an antiviral agent; a vaccine specific for RSV, a vaccinespecific for influenza virus, or a vaccine specific for metapneumovirus(MPV); an siRNA specific for an RSV antigen or a metapneumovirus (MPV)antigen; a second antibody specific for an RSV antigen or ametapneumovirus (MPV) antigen; an anti-IL4R antibody, an antibodyspecific for an influenza virus antigen, an anti-RSV-G antibody and aNSAID.

In certain embodiments are provided pharmaceutical compositionscomprising any one or more of the isolated antibodies or antigen-bindingfragments thereof and a pharmaceutically acceptable carrier and/orexcipient.

In certain embodiments are provided pharmaceutical compositionsaccording to other embodiments for use in preventing a respiratorysyncytial virus (RSV) infection in a patient in need thereof orsuspected of being in need thereof, or for treating a patient sufferingfrom an RSV infection, or for ameliorating at least one symptom orcomplication associated with the infection, wherein the infection iseither prevented, or at least one symptom or complication associatedwith the infection is prevented, ameliorated, or lessened in severityand/or duration as a result of such use.

In certain embodiments are provided pharmaceutical compositionsaccording to other embodiments for use in treating or preventing eithera Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus(HMPV) infection, ar at least one symptom associated with said RSVinfection or said HMPV infection, in a patient in need thereof orsuspected of being in need thereof, wherein the infection is eitherprevented, or at least one symptom or complication associated with theinfection is prevented, ameliorated, or lessened in severity and/orduration as a result of such use.

In certain other embodiments are provided uses of the pharmaceuticalcompositions according to other embodiments in the manufacture of amedicament for preventing a respiratory syncytial virus (RSV) infectionin a patient in need thereof, or for treating a patient suffering froman RSV infection, or for ameliorating at least one symptom orcomplication associated with the infection, wherein the infection iseither prevented, or at least one symptom or complication associatedwith the infection is prevented, ameliorated, or lessened in severityand/or duration.

In certain other embodiments are provided uses of the pharmaceuticalcompositions according to other embodiments in the manufacture of amedicament for preventing either a Respiratory Syncytial Virus (RSV)infection or a human metapneumovirus (HMPV) infection, ar at least onesymptom associated with said RSV infection or said HMPV infection, in apatient in need thereof or suspected of being in need thereof, whereinthe infection is either prevented, or at least one symptom orcomplication associated with the infection is prevented, ameliorated, orlessened in severity and/or duration as a result of such use.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A through FIG. 1F illustrates the anti-RSV repertoire cloning andsequence analysis of the identified and isolated antibodies. FIG. 1A:RSV F-specific B cell sorting. FACS plots show RSV F reactivity of IgG⁺and IgA⁺ B cells from the healthy adult donor. B cells in quadrant 2(Q2) were single cell sorted. FIG. 1B: Isotype analysis. Index sortplots show the percentage of RSV F-specific B cells that express IgG orIgA. FIG. 1C: Clonal lineage analysis. Each slice represents one clonallineage; the size of the slice is proportional to the number of clonesin the lineage. The total number of clones is shown in the center of thepie. Clonal lineages were assigned based on the following criteria: 1)matching of variable and joining gene segments; 2) identical CDR3 looplengths; and 3) >80% homology in CDR3 nucleotide sequences. FIG. 1D: VHrepertoire analysis. VH germline genes were considered to be enriched inthe RSV repertoire if the a given gene was found to be enriched bygreater than 3-fold over non-RSV-specific repertoires (33). FIG. 1E:CDRH3 length distribution. FIG. 1F: Somatic hypermutation in VH(excluding CDRH3). Red bars indicate the average number of nucleotidesubstitutions. Each clonal lineage is only represented once in (D) and(E). Data for non-RSV reactive IgGs were derived from publishedsequences obtained by high-throughput sequencing of re-arranged antibodyvariable gene repertoires from healthy individuals (33).

FIG. 2A through 2D illustrates the similar antibody preferences observedfor conformational state and subtype of RSV F in the repertoire. FIG.2A: IgG affinities for preF and postF are plotted as shown. FIG. 2B:Percentage of antibodies within the donor repertoire that recognizedboth conformations of F (green) or bind only to preF (blue) or postF(orange). FIG. 2C: Percentage of antibodies within the donor repertoirethat bind specifically to subtype A (green), subtype B (blue), or bothsubtypes A and B (red). N.B., non-binder. IgG KDs were calculated forantibodies with BLI responses >0.1 nm. Antibodies with BLI responses<0.05 nm were designated as N.B. FIG. 2D: Polyreactivity analysis ofanti-RSV antibodies. The polyreactivity of the isolated anti-RSV Fantibodies was measured using a previously described assay (42, 43).Three panels of control antibodies were included for comparison: a groupof 138 antibodies currently in clinical trials, 39 antibodies that havebeen approved for clinical use and 14 broadly neutralizing HIVantibodies.

FIG. 3A through FIG. 3G illustrate mapping and specificities of anti-RSVantibodies for antigenic sites spanning the surface of PreF and PostF.FIG. 3A: The previously determined structure of preF with one protomershown as ribbons and with six antigenic sites rainbow colored from redto purple. FIG. 3B: The percentage of antibodies targeting eachantigenic site is shown. FIG. 3C: Percentage of preF-specific antibodiestargeting each antigenic site. FIG. 3D: Apparent antibody bindingaffinities for subtype A PreF antigenic sites. FIG. 3E: Apparent bindingaffinities for subtype A postF antigenic sites. FIG. 3F: Apparentantibody binding affinities for subtype B PreF antigenic sites. FIG. 3G.Apparent binding affinities for subtype B postF. Only antibodies withapparent binding affinities greater than 2 nM were included in thisanalysis, since antibodies with lower affinity could not be reliablymapped. Red bars show the median and the dotted grey line is at 2 nM.N.B., non-binder.

FIG. 4A through FIG. 4G illustrate neutralizing potencies of anti-RSVantibodies and correlation between potency and Pref vs. PostF specifityfor each of RSV subtypes A and B. FIG. 4A: Neutralization IC₅₀s for theantibodies isolated from the donor repertoire. Data points are coloredbased on neutralization potency, according to the legend on the right.Red and blue dotted lines depict motavizumab and D25 IC₅₀s,respectively. FIG. 4B: Percentage of neutralizing antibodies in thedonor repertoire against RSV subtype A or subtype B, stratified bypotency as indicated in the legend in the right portion of the figure.FIG. 4C: Percentage of antibodies within the donor repertoire thatneutralized both RSV subtypes A and B (red) or neutralized only RSVsubtype A (green) or subtype B (blue). FIG. 4D: Apparent bindingaffinities for subtype A, preF and postF, plotted for each antibody (IgGKDs were calculated for antibodies with BLI responses >0.1 nm.Antibodies with BLI responses <0.05 nm were designated as N.B.) FIG. 4E:Neutralization IC₅₀s plotted for RSV subtype A preF-specific,postF-specific, and cross-reactive antibodies. (Red and blue dottedlines depict motavizumab and D25 IC₅₀s, respectively. Red bars depictmedian. N.B., non-binder; N.N., non-neutralizing). FIG. 4F: Apparentantibody binding affinities for subtype B, preF and postF. FIG. 4G:IC₅₀s plotted for RSV subtype B preF-specific, postF-specific andcross-reactive antibodies. (Black bar depicts median. N.B., non-binder;N.N., non-neutralizing.)

FIG. 5A through FIG. 5C illustrate that the most potent neutralizingantibodies bind with high affinity to preF and recognize antigenic sitesØ and V. FIG. 5A: apparent preF K_(D) plotted against neutralizationIC₅₀ and colored according to antigenic site, as shown in the legend atright of FIG. 5C. FIG. 5B: apparent postF K_(D) plotted againstneutralization IC₅₀ and colored as in FIG. 5A. FIG. 5C: antibodiesgrouped according to neutralization potency and colored by antigenicsite as in legend at right. N.B., non-binder; N.N., non-neutralizing.IgG KDs were calculated for antibodies with BLI responses >0.1 nm.Antibodies with BLI responses <0.05 nm were designated as N.B.Statistical significance was determined using an unpaired two-tailed ttest. The Pearson's correlation coefficient, r, was calculated usingPrism software version 7.0. Antibodies that failed to bind or neutralizewere excluded from the statistical analysis due to the inability toaccurately calculate midpoint concentrations.

FIG. 6A through FIG. 6C illustrate the nature and purification of pre-and postF sorting probes. FIG. 6A: Schematic of fluorescent prefusionRSV F probe shows one PE-conjugated streptavidin molecule bound by fouravi-tagged trimeric prefusion F molecules. FIG. 6B: Coomassie-stainedSDS-PAGE gel demonstrating the isolation of RSV F with a single AviTagper trimer using sequential Ni-NTA and Strep-Tactin purifications, asdescribed in the Methods. FIG. 6C: Fluorescence size-exclusionchromatography (FSEC) trace of the tetrameric probes on a Superose 6column. Positions of molecular weight standards are indicated witharrows.

FIG. 7A through FIG. 7C illustrates the generation and validation ofpreF patch panel mutants. FIG. 7A: Panel of RSV F variants used forepitope mapping. FIG. 7B: Prefusion RSV F shown as molecular surfacewith one protomer colored in white. The nine variants, each containing apatch of mutations, are uniquely colored according to the table in FIG.7A. FIG. 7C: Binding of each IgG to fluorescently labeled beads coupledto each of the variants listed in FIG. 7A was measured usingPE-conjugated anti-human Fc antibody on a FLEXMAP 3D flow cytometer(Luminex). Reduced binding of D25 and motavizumab to patches 1 and 5,respectively, is consistent with their structurally defined epitopes(10, 11). AM14 binding was reduced for both patch 3 and patch 9, due toits unique protomer-spanning epitope (21). This characteristic bindingprofile was used to assist in the classification of other possiblequaternary-specific antibodies in the panel.

FIG. 8 illustrates the antigenic site V resides between the epitopesrecognized by D25, MPE8 and motavizumab. Prefusion F is shown with onepromoter as a cartoon colored according to antigenic site location andthe other two protomers colored grey. D25 and motavizumab Fabs are shownin blue and pink, respectively. The MPE8 binding site is circled inblack. Antigenic site V is located between the binding sites of D25 andMPE8 within one protomer, explaining the competition between site-Vdirected antibodies and these controls. Competition with motavizumab mayoccur across two adjacent protomers (left) or within one protomer(right), depending on the angle-of-approach of these site-V directedantibodies.

FIG. 9 illustrates percentage of anti-RSV antibodies demonstrating theindicated neutralizing activities of preF-specific, postF-specific, andcross-reactive antibodies. Antibodies were stratified according toneutralization potency and the percentage of antibodies in each groupthat were preF-specific (pink), postF-specific (white) or cross-reactive(orange) were plotted for subtype A (left panel) and subtype B (rightpanel).

FIG. 10A through FIG. 10C illustrates the relationship between subtype Bneutralization and antigenic site specificity for anti-RSV antibodies.FIG. 10A: Subtype B preF affinity plotted against neutralization IC₅₀for all antibodies and colored by antigenic site according to the colorescheme depicted in FIG. 10C, right portion. FIG. 10B: PostF affinityplotted against IC50 and colored as in FIG. 10A. FIG. 10C: Antibodieswith preF affinities higher than 2 nM grouped according toneutralization potency and colored by antigenic site (right portion).

FIG. 11 illustrates in vitro neutralization of RSV A2 for specificanti-RSV antibodies. Inhibition of RSV-replication was measured in anELISA based neutralization Assay using Hep-2 cells. Cells, mAbs andviruses were co-incubated for 4 days at 37° C., followed byquantification of viral proteins in infected cells using a polyclonalanti-RSV antibody. % inhibition was calculated relative to control cellsinfected with virus in absence of neutralizing antibody. Data areexpressed as half-maximal inhibitory concentration that resulted in 50%reduction in virus replication (IC50) and represent the mean+/−SEM oftwo independent experiments. An isotype matched control mAb (*) wasincluded in every experiment and did not exhibit virus neutralization.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. As used herein, the term“about,” when used in reference to a particular recited numerical value,means that the value may vary from the recited value by no more than 1%.For example, as used herein, the expression “about 100” includes 99 and101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

Definitions

“Respiratory Syncytial Virus-F protein”, also referred to as “RSV-F” isa type I transmembrane surface protein, which has an N terminal cleavedsignal peptide and a membrane anchor near the C terminus (Collins, P. L.et al., (1984), PNAS (USA) 81:7683-7687). The RSV-F protein issynthesized as an inactive 67 KDa precursor denoted as F0 (Calder, L.J.; et al., Virology (2000), 277,122-131. The F0 protein is activatedproteolytically in the Golgi complex by a furin-like protease at twosites, yielding two disulfide linked polypeptides, F2 and F1, from the Nand C terminal, respectively. There is a 27 amino acid peptide releasedcalled “pep27”. There are furin cleavage sites (FCS) on either side ofthe pep27 (Collins, P. L.; Mottet, G. (1991), J. Gen. Virol., 72:3095-3101; Sugrue, R. J, et al. (2001), J. Gen. Virol., 82,1375-1386).The F2 subunit consists of the Heptad repeat C (HRC), while the F1contains the fusion polypeptide (FP), heptad repeat A (HRA), domain I,domain II, heptad repeat B (HRB), transmembrane (TM) and cytoplasmicdomain (CP) (See Sun, Z. et al. Viruses (2013), 5:21 1-225). The RSV-Fprotein plays a role in fusion of the virus particle to the cellmembrane, and is expressed on the surface of infected cells, thusplaying a role in cell to cell transmission of the virus and syncytiaformation. The amino acid sequence of the RSV-F protein is provided inGenBank as accession number AAX23994.

A stabilized variant of the PreF trimeric conformation of RSV-F, termed“RSV-DS-Cav1”, or “DS-Cav1” disclosed in, inter alia, Stewart-Jones etal., PLos One, Vol. 10(6)):e0128779. doi: 10.1371/journal.pone.0128779and WO 2011/050168. was used in the identification, isolation, andcharacterization of the antibodies disclosed herein.

The term “laboratory strain” as used herein refers to a strain of RSV(subtype A or B) that has been passaged extensively in in vitro cellculture. A “laboratory strain” can acquire adaptive mutations that mayaffect their biological properties. A “clinical strain” as used hereinrefers to an RSV isolate (subtype A or B), which is obtained from aninfected individual and which has been isolated and grown in tissueculture at low passage.

The term “effective dose 99” or “ED₉₉” refers to the dosage of an agentthat produces a desired effect of 99% reduction of viral forming plaquesrelative to the isotype (negative) control. In the present invention,the ED₉₉ refers to the dosage of the anti-RSV-F antibodies that willneutralize the virus infection (e.g. reduce 99% of viral load) in vivo,as described in Example 5.

The term “IC₅₀” refers to the “half maximal inhibitory concentration”,which value measures the effectiveness of compound (e.g. anti-RSV-Fantibody) inhibition towards a biological or biochemical utility. Thisquantitative measure indicates the quantity required for a particularinhibitor to inhibit a given biological process by half. In certainembodiments, RSV virus neutralization potencies for anti-RSV and/oranti-RSV/anti-HMPV cross-neutralizing antibodies disclosed herein areexpressed as neutralization IC₅₀ values.

“Palivizumab”, also referred to as “SYNAGIS®”, is a humanized anti-RSV-Fantibody with heavy and light chain variable domains having the aminoacid sequences as set forth in U.S. Pat. Nos. 7,635,568 and 5,824,307.This antibody, which immunospecifically binds to the RSV-F protein, iscurrently FDA-approved for the passive immunoprophylaxis of serious RSVdisease in high-risk children and is administered intramuscularly atrecommended monthly doses of 15 mg/kg of body weight throughout the RSVseason (November through April in the northern hemisphere). SYNAGIS® iscomposed of 95% human and 5% murine antibody sequences. See also Johnsonet al., (1997), J. Infect. Diseases 176:1215-1224.

“Motavizumab”, also referred to as “NUMAX™”, is an enhanced potencyRSV-F-specific humanized monoclonal antibody derived by in vitroaffinity maturation of the complementarity-determining regions of theheavy and light chains of palivizumab. For reference purposes, the aminoacid sequence of the NUMAX™ antibody is disclosed in U.S. PatentPublication 2003/0091584 and in U.S. Pat. No. 6,818,216 and in Wu etal., (2005) J. Mol. Bio. 350(1):126-144 and in Wu, et al. (2007) J. Mol.Biol. 368:652-665. It is also shown herein as SEQ ID NO: 359 for theheavy chain and as SEQ ID NO: 360 for the light chain of the antibody.

As used herein, the terms “treat,” “treatment” and “treating” refer tothe reduction or amelioration of the progression, severity, and/orduration of an upper and/or lower respiratory tract RSV infection and/orhuman metapneumovirus (HMPV), otitis media, or a symptom or respiratorycondition related thereto (such as asthma, wheezing, or a combinationthereof) resulting from the administration of one or more therapies(including, but not limited to, the administration of one or moreprophylactic or therapeutic agents). In certain embodiments, such termsrefer to the reduction or inhibition of the replication of RSV and/orHMPV, the inhibition or reduction in the spread of RSV and/or HMPV toother tissues or subjects (e.g., the spread to the lower respiratorytract), the inhibition or reduction of infection of a cell with a RSVand/or HMPV, or the amelioration of one or more symptoms associated withan upper and/or lower respiratory tract RSV infection or otitis media.

As used herein, the terms “prevent,” “preventing,” and “prevention”refer to the prevention or inhibition of the development or onset of anupper and/or lower respiratory tract RSV and/or HMPV infection, otitismedia or a respiratory condition related thereto in a subject, theprevention or inhibition of the progression of an upper respiratorytract RSV and/or HMPV infection to a lower respiratory tract RSV and/orHMPV infection, otitis media or a respiratory condition related theretoresulting from the administration of a therapy (e.g., a prophylactic ortherapeutic agent), the prevention of a symptom of an upper and/or lowertract RSV and/or HMPV infection, otitis media or a respiratory conditionrelated thereto, or the administration of a combination of therapies(e.g., a combination of prophylactic or therapeutic agents). As usedherein, the terms “ameleliorate” and “alleviate” refer to a reduction ordiminishment in the severity a condition or any symptoms thereof.

The term “antibody”, as used herein, is intended to refer toimmunoglobulin molecules comprised of four polypeptide chains, two heavy(H) chains and two light (L) chains interconnected by disulfide bonds(i.e., “full antibody molecules”), as well as multimers thereof (e.g.IgM) or antigen-binding fragments thereof. Each heavy chain is comprisedof a heavy chain variable region (“HCVR” or “V_(H)”) and a heavy chainconstant region (comprised of domains C_(H)1, C_(H)2 and C_(H)3). Eachlight chain is comprised of a light chain variable region (“LCVR or“V_(L)”) and a light chain constant region (C_(L)). The V_(H) and V_(L)regions can be further subdivided into regions of hypervariability,termed complementarity determining regions (CDR), interspersed withregions that are more conserved, termed framework regions (FR). EachV_(H) and V_(L) is composed of three CDRs and four FRs, arranged fromamino-terminus to carboxy-terminus in the following order: FR1, CDR1,FR2, CDR2, FR3, CDR3, FR4. In certain embodiments of the invention, theFRs of the antibody (or antigen binding fragment thereof) may beidentical to the human germline sequences, or may be naturally orartificially modified. An amino acid consensus sequence may be definedbased on a side-by-side analysis of two or more CDRs. Accordingly, theCDRs in a heavy chain are designated “CHRH1”, “CDRH2”, and “CDRH3”,respectively, and the CDRs in a light chain are designated “CDRL1”,“CDRL2”, and “CDRL3”.

Substitution of one or more CDR residues or omission of one or more CDRsis also possible. Antibodies have been described in the scientificliterature in which one or two CDRs can be dispensed with for binding.Padlan et al. (1995 FASEB J. 9:133-139) analyzed the contact regionsbetween antibodies and their antigens, based on published crystalstructures, and concluded that only about one fifth to one third of CDRresidues actually contact the antigen. Padlan also found many antibodiesin which one or two CDRs had no amino acids in contact with an antigen(see also, Vajdos et al. 2002 J Mol Biol 320:415-428).

CDR residues not contacting antigen can be identified based on previousstudies (for example residues H60-H65 in CDRH2 are often not required),from regions of Kabat CDRs lying outside Chothia CDRs, by molecularmodeling and/or empirically. If a CDR or residue(s) thereof is omitted,it is usually substituted with an amino acid occupying the correspondingposition in another human antibody sequence or a consensus of suchsequences. Positions for substitution within CDRs and amino acids tosubstitute can also be selected empirically.

The fully human monoclonal antibodies disclosed herein may comprise oneor more amino acid substitutions, insertions and/or deletions in theframework and/or CDR regions of the heavy and light chain variabledomains as compared to the corresponding germline sequences. Suchmutations can be readily ascertained by comparing the amino acidsequences disclosed herein to germline sequences available from, forexample, public antibody sequence databases. The present inventionincludes antibodies, and antigen-binding fragments thereof, which arederived from any of the amino acid sequences disclosed herein, whereinone or more amino acids within one or more framework and/or CDR regionsare mutated to the corresponding residue(s) of the germline sequencefrom which the antibody was derived, or to the corresponding residue(s)of another human germline sequence, or to a conservative amino acidsubstitution of the corresponding germline residue(s) (such sequencechanges are referred to herein collectively as “germline mutations”). Aperson of ordinary skill in the art, starting with the heavy and lightchain variable region sequences disclosed herein, can easily producenumerous antibodies and antigen-binding fragments which comprise one ormore individual germline mutations or combinations thereof. In certainembodiments, all of the framework and/or CDR residues within the V_(H)and/or V_(L) domains are mutated back to the residues found in theoriginal germline sequence from which the antibody was derived. In otherembodiments, only certain residues are mutated back to the originalgermline sequence, e.g., only the mutated residues found within thefirst 8 amino acids of FR1 or within the last 8 amino acids of FR4, oronly the mutated residues found within CDR1, CDR2 or CDR3. In otherembodiments, one or more of the framework and/or CDR residue(s) aremutated to the corresponding residue(s) of a different germline sequence(i.e., a germline sequence that is different from the germline sequencefrom which the antibody was originally derived). Furthermore, theantibodies of the present invention may contain any combination of twoor more germline mutations within the framework and/or CDR regions,e.g., wherein certain individual residues are mutated to thecorresponding residue of a particular germline sequence while certainother residues that differ from the original germline sequence aremaintained or are mutated to the corresponding residue of a differentgermline sequence. Once obtained, antibodies and antigen-bindingfragments that contain one or more germline mutations can be easilytested for one or more desired property such as, improved bindingspecificity, increased binding affinity, improved or enhancedantagonistic or agonistic biological properties (as the case may be),reduced immunogenicity, etc. Antibodies and antigen-binding fragmentsobtained in this general manner are encompassed within the presentinvention.

The present invention also includes fully monoclonal antibodiescomprising variants of any of the CDR amino acid sequences disclosedherein having one or more conservative substitutions. For example, thepresent invention includes antibodies having CDR amino acid sequenceswith, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc.conservative amino acid substitutions relative to any of the CDR aminoacid sequences disclosed herein.

The term “human antibody”, as used herein, is intended to includeantibodies having variable and constant regions derived from humangermline immunoglobulin sequences. The human mAbs of the invention mayinclude amino acid residues not encoded by human germline immunoglobulinsequences {e.g., mutations introduced by random or site-specificmutagenesis in vitro or by somatic mutation in vivo), for example in theCDRs and in particular CDR3.

However, the term “human antibody”, as used herein, is not intended toinclude mAbs in which CDR sequences derived from the germline of anothermammalian species (e.g., mouse), have been grafted onto human FRsequences.

The term “humanized antibody” refers to human antibody in which one ormore CDRs of such antibody have been replaced with one or morecorresponding CDRs obtained a non-human derived (e.g., mouse, rat,rabbit, primate) antibody. Humanized antibodies may also include certainnon-CDR sequences or residues derived from such non-human antibodies aswell as the one or more non-human CDR sequence. Such antibodies may alsobe referred to as “chimeric” antibodies.

The term “recombinant” generally refers to any protein, polypeptide, orcell expressing a gene of interest that is produced by geneticengineering methods. The term “recombinant” as used with respect to aprotein or polypeptide, means a polypeptide produced by expression of arecombinant polynucleotide. The proteins used in the immunogeniccompositions of the invention may be isolated from a natural source orproduced by genetic engineering methods.

The antibodies of the invention may, in some embodiments, be recombinanthuman antibodies. The term “recombinant human antibody”, as used herein,is intended to include all antibodies, including human or humanizedantibodies, that are prepared, expressed, created or isolated byrecombinant means, such as antibodies expressed using a recombinantexpression vector transfected into a host cell (described furtherbelow), antibodies isolated from a recombinant, combinatorial humanantibody library (described further below), antibodies isolated from ananimal (e.g., a mouse) that is transgenic for human immunoglobulin genes(see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) orantibodies prepared, expressed, created or isolated by any other meansthat involves splicing of human immunoglobulin gene sequences to otherDNA sequences. Such recombinant human antibodies have variable andconstant regions derived from human germline immunoglobulin sequences.In certain embodiments, however, such recombinant human antibodies aresubjected to in vitro mutagenesis (or, when an animal transgenic forhuman Ig sequences is used, in vivo somatic mutagenesis) and thus theamino acid sequences of the V_(H) and V_(L) regions of the recombinantantibodies are sequences that, while derived from and related to humangermline V_(H) and V_(L) sequences, may not naturally exist within thehuman antibody germline repertoire in vivo.

The term “specifically binds,” or “binds specifically to”, or the like,means that an antibody or antigen-binding fragment thereof forms acomplex with an antigen that is relatively stable under physiologicconditions. Specific binding can be characterized by an equilibriumdissociation constant of at least about 1×10⁻⁶ M or less (e.g., asmaller K_(D) denotes a tighter binding). Methods for determiningwhether two molecules specifically bind are well known in the art andinclude, for example, equilibrium dialysis, surface plasmon resonance,and the like. As described herein, antibodies have been identified bysurface plasmon resonance, e.g., BIACORE™, biolayer interferometrymeasurements using, e.g., a ForteBio Octet HTX instrument (Pall LifeSciences), which bind specifically to RSV-F. Moreover, multi-specificantibodies that bind to RSV-F protein and one or more additionalantigens, such as an antigen expressed by HMPV, or a bi-specific thatbinds to two different regions of RSV-F are nonetheless consideredantibodies that “specifically bind”, as used herein. In certainembodiments, the antibodies disclosed herein display equilibriumdissociation constants (and hence specificities) of about 1×10-⁶ M;about 1×10-⁷ M; about 1×10-⁸ M; about 1×10-⁹ M; about 1×10-¹⁰ M; betweenabout 1×10⁻⁶ M and about 1×10-⁷ M; between about 1×10-⁷M and about1×10-⁸ M; between about 1×10-⁸ M and about 1×10-⁹ M; or between about1×10-⁹ M and about 1×10-¹⁰ M.

The term “high affinity” antibody refers to those mAbs having a bindingaffinity to RSV-F and/or HMPV, expressed as K_(D), of at least 10-⁹ M;more preferably 10-¹⁰M, more preferably 10⁻¹¹M, more preferably 10⁻¹²Mas measured by surface plasmon resonance, e.g., BIACORE™ biolayerinterferometry measurements using, e.g., a ForteBio Octet HTX instrument(Pall Life Sciences), or solution-affinity ELISA.

By the term “slow off rate”, “Koff” or “kd” is meant an antibody thatdissociates from RSV-F, with a rate constant of 1×10⁻³ s^(″1) or less,preferably 1×10⁻⁴ s^(″1) or less, as determined by surface plasmonresonance, e.g., BIACORE™ or a ForteBio Octet HTX instrument (Pall LifeSciences).

The terms “antigen-binding portion” of an antibody, “antigen-bindingfragment” of an antibody, and the like, as used herein, include anynaturally occurring, enzymatically obtainable, synthetic, or geneticallyengineered polypeptide or glycoprotein that specifically binds anantigen to form a complex. In certain embodiments, the terms“antigen-binding portion” of an antibody, or “antibody fragment”, asused herein, refers to one or more fragments of an antibody that retainsthe ability to bind to RSV-F and/or HMPV.

An antibody fragment may include a Fab fragment, a F(ab′)₂ fragment, aFv fragment, a dAb fragment, a fragment containing a CDR, or an isolatedCDR. Antigen-binding fragments of an antibody may be derived, e.g., fromfull antibody molecules using any suitable standard techniques such asproteolytic digestion or recombinant genetic engineering techniquesinvolving the manipulation and expression of DNA encoding antibodyvariable and (optionally) constant domains. Such DNA is known and/or isreadily available from, e.g., commercial sources, DNA libraries(including, e.g., phage-antibody libraries), or can be synthesized. TheDNA may be sequenced and manipulated chemically or by using molecularbiology techniques, for example, to arrange one or more variable and/orconstant domains into a suitable configuration, or to introduce codons,create cysteine residues, modify, add or delete amino acids, etc.

Non-limiting examples of antigen-binding fragments include: (i) Fabfragments; (ii) F(ab′)2 fragments; (iii) Fd fragments; (iv) Fvfragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and(vii) minimal recognition units consisting of the amino acid residuesthat mimic the hypervariable region of an antibody (e.g., an isolatedcomplementarity determining region (CDR) such as a CDR3 peptide), or aconstrained FR3-CDR3-FR4 peptide. Other engineered molecules, such asdomain-specific antibodies, single domain antibodies, domain-deletedantibodies, chimeric antibodies, CDR-grafted antibodies, diabodies,triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalentnanobodies, bivalent nanobodies, etc.), small modularimmunopharmaceuticals (SMIPs), and shark variable IgNAR domains, arealso encompassed within the expression “antigen-binding fragment,” asused herein.

An antigen-binding fragment of an antibody will typically comprise atleast one variable domain. The variable domain may be of any size oramino acid composition and will generally comprise at least one CDR,which is adjacent to or in frame with one or more framework sequences.In antigen-binding fragments having a V_(H) domain associated with aV_(L) domain, the V_(H) and V|_ domains may be situated relative to oneanother in any suitable arrangement. For example, the variable regionmay be dimeric and contain V_(H)-V_(H), V_(H)-V_(L) or V_(L)-V_(L)dimers. Alternatively, the antigen-binding fragment of an antibody maycontain a monomeric V_(H) or V_(L) domain.

In certain embodiments, an antigen-binding fragment of an antibody maycontain at least one variable domain covalently linked to at least oneconstant domain. Non-limiting, exemplary configurations of variable andconstant domains that may be found within an antigen-binding fragment ofan antibody of the present invention include: (i) V_(H)-C_(H)1; (ii)V_(H)-C_(H)2; (iii) V_(H)-C_(H)3; (iv) V_(H)-C_(h)1-C_(h)2; (V)V_(H)-C_(h)1-C_(h)2-C_(h)3; (vi) V_(H)-C_(H)2-C_(H)3; (vii) V_(H)-C_(L);(viii) V_(L)-C_(H)1; (ix) V_(L)-C_(H)2; (x) V_(L)-C_(H)3; (xi)V_(L)-C_(H)1-C_(H)2; (xii) V_(L)-C_(H)1-C_(H)2-C_(H)3; (xiii)V_(L)-C_(H)2-C_(H)3; and (Xiv) V_(L)-C_(L). In any configuration ofvariable and constant domains, including any of the exemplaryconfigurations listed above, the variable and constant domains may beeither directly linked to one another or may be linked by a full orpartial hinge or linker region. A hinge region may consist of at least 2(e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which result in aflexible or semi-flexible linkage between adjacent variable and/orconstant domains in a single polypeptide molecule. Moreover, anantigen-binding fragment of an antibody of the present invention maycomprise a homo-dimer or hetero-dimer (or other multimer) of any of thevariable and constant domain configurations listed above in non-covalentassociation with one another and/or with one or more monomeric V_(H) orV_(L) domain (e.g., by disulfide bond(s)).

As with full antibody molecules, antigen-binding fragments may bemono-specific or multi-specific (e.g., bi-specific). A multi-specificantigen-binding fragment of an antibody will typically comprise at leasttwo different variable domains, wherein each variable domain is capableof specifically binding to a separate antigen or to a different epitopeon the same antigen. Any multi-specific antibody format, including theexemplary bi-specific antibody formats disclosed herein, may be adaptedfor use in the context of an antigen-binding fragment of an antibody ofthe present invention using routine techniques available in the art.

The specific embodiments, antibody or antibody fragments of theinvention may be conjugated to a therapeutic moiety (“immunoconjugate”),such as an antibiotic, a second anti-RSV-F antibody, an anti-HMPVantibody, a vaccine, or a toxoid, or any other therapeutic moiety usefulfor treating an RSV infection and/or an HMPV infection.

An “isolated antibody”, as used herein, is intended to refer to anantibody that is substantially free of other antibodies (Abs) havingdifferent antigenic specificities (e.g., an isolated antibody thatspecifically binds RSV-F and/or HMPV, or a fragment thereof, issubstantially free of Abs that specifically bind antigens other thanRSV-F and/or HMPV.

A “blocking antibody” or a “neutralizing antibody”, as used herein (oran “antibody that neutralizes RSV-F and/or HMPVactivity”), is intendedto refer to an antibody whose binding to RSV-F or to an HMPV antigen, asthe case may be as disclosed herein, results in inhibition of at leastone biological activity of RSV-F and/or HMPV. For example, an antibodyof the invention may aid in blocking the fusion of RSV and/or HMPV to ahost cell, or prevent syncytia formation, or prevent the primary diseasecaused by RSV and/or HMPV. Alternatively, an antibody of the inventionmay demonstrate the ability to ameliorate at least one symptom of theRSV infection and or HMPV infection. This inhibition of the biologicalactivity of RSV-F and/or HMPV can be assessed by measuring one or moreindicators of RSV-F and/or HMPV biological activity by one or more ofseveral standard in vitro assays (such as a neutralization assay, asdescribed herein) or in vivo assays known in the art (for example,animal models to look at protection from challenge with RSV and/or HMPVfollowing administration of one or more of the antibodies describedherein).

The term “surface plasmon resonance”, as used herein, refers to anoptical phenomenon that allows for the analysis of real-timebiomolecular interactions by detection of alterations in proteinconcentrations within a biosensor matrix, for example using the BIACORE™system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.).

The term “K_(D)”, as used herein, is intended to refer to theequilibrium dissociation constant of a particular antibody-antigeninteraction.

The term “epitope” refers to an antigenic determinant that interactswith a specific antigen binding site in the variable region of anantibody molecule known as a paratope. A single antigen may have morethan one epitope. Thus, different antibodies may bind to different areason an antigen and may have different biological effects. The term“epitope” also refers to a site on an antigen to which B and/or T cellsrespond. It also refers to a region of an antigen that is bound by anantibody. Epitopes may be defined as structural or functional.Functional epitopes are generally a subset of the structural epitopesand have those residues that directly contribute to the affinity of theinteraction. Epitopes may also be conformational, that is, composed ofnon-linear amino acids. In certain embodiments, epitopes may includedeterminants that are chemically active surface groupings of moleculessuch as amino acids, sugar side chains, phosphoryl groups, or sulfonylgroups, and, in certain embodiments, may have specific three-dimensionalstructural characteristics, and/or specific charge characteristics.

The term “substantial identity”, or “substantially identical,” whenreferring to a nucleic acid or fragment thereof, indicates that, whenoptimally aligned with appropriate nucleotide insertions or deletionswith another nucleic acid (or its complementary strand), there isnucleotide sequence identity in at least about 90%, and more preferablyat least about 95%, 96%, 97%, 98% or 99% of the nucleotide bases, asmeasured by any well-known algorithm of sequence identity, such asFASTA, BLAST or GAP, as discussed below. Accordingly, nucleic acidsequences that display a certain percentage “identity” share thatpercentage identity, and/or are that percentage “identical” to oneanother. A nucleic acid molecule having substantial identity to areference nucleic acid molecule may, in certain instances, encode apolypeptide having the same or substantially similar amino acid sequenceas the polypeptide encoded by the reference nucleic acid molecule.

In certain embodiments, the disclosed antibody nucleic acid sequencesare, e.g.: at least 70% identical; at least 75% identical; 80%identical; at least 85% identical; at least 90% identical; at least 95%identical; at least 96% identical; at least 97% identical; at least 98%identical; at least 99%; and/or all percentages of identity in between;to other sequences and/or share such percentage identities with oneanother (or with certain subsets of the herein-disclosed antibodysequences).

As applied to polypeptides, the term “substantial identity” or“substantially identical” means that two peptide sequences, whenoptimally aligned, such as by the programs GAP or BESTFIT using defaultgap weights, share at least 90% sequence identity, even more preferablyat least 95%, 98% or 99% sequence identity. Accordingly, amino acidsequences that display a certain percentage “identity” share thatpercentage identity, and/or are that percentage “identical” to oneanother. Accordingly, amino acid sequences that display a certainpercentage “identity” share that percentage identity, and/or are thatpercentage “identical” to one another.

In certain embodiments, the disclosed antibody amino acid sequences are,e.g.: at least 70% identical; at least 75% identical; 80% identical; atleast 85% identical; at least 90% identical; at least 95% identical; atleast 96% identical; at least 97% identical; at least 98% identical; atleast 99%; and/or all percentages of identity in between; to othersequences and/or share such percentage identities with one another (orwith certain subsets of the herein-disclosed antibody sequences).

Preferably, residue positions, which are not identical, differ byconservative amino acid substitutions. A “conservative amino acidsubstitution” is one in which an amino acid residue is substituted byanother amino acid residue having a side chain (R group) with similarchemical properties (e.g., charge or hydrophobicity). In general, aconservative amino acid substitution will not substantially change thefunctional properties of a protein. In cases where two or more aminoacid sequences differ from each other by conservative substitutions, thepercent or degree of similarity may be adjusted upwards to correct forthe conservative nature of the substitution. Means for making thisadjustment are well known to those of skill in the art. (See, e.g.,Pearson (1994) Methods Mol. Biol. 24: 307-331). Examples of groups ofamino acids that have side chains with similar chemical propertiesinclude 1) aliphatic side chains: glycine, alanine, valine, leucine andisoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3)amide-containing side chains: asparagine and glutamine; 4) aromatic sidechains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains:lysine, arginine, and histidine; 6) acidic side chains: aspartate andglutamate, and 7) sulfur-containing side chains: cysteine andmethionine. Preferred conservative amino acids substitution groups are:valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine,alanine-valine, glutamate-aspartate, and asparagine-glutamine.Alternatively, a conservative replacement is any change having apositive value in the PAM250 log-likelihood matrix disclosed in Gonnetet al. (1992) Science 256: 1443 45. A “moderately conservative”replacement is any change having a nonnegative value in the PAM250log-likelihood matrix.

Sequence similarity for polypeptides is typically measured usingsequence analysis software. Protein analysis software matches similarsequences using measures of similarity assigned to varioussubstitutions, deletions and other modifications, including conservativeamino acid substitutions. For instance, GCG software contains programssuch as GAP and BESTFIT which can be used with default parameters todetermine sequence homology or sequence identity between closely relatedpolypeptides, such as homologous polypeptides from different species oforganisms or between a wild type protein and a mutein thereof. See,e.g., GCG Version 6.1. Polypeptide sequences also can be compared usingFASTA with default or recommended parameters; a program in GCG Version6.1. FASTA {e.g., FASTA2 and FASTA3) provides alignments and percentsequence identity of the regions of the best overlap between the queryand search sequences (Pearson (2000) supra). Another preferred algorithmwhen comparing a sequence of the invention to a database containing alarge number of sequences from different organisms is the computerprogram BLAST, especially BLASTP or TBLASTN, using default parameters.(See, e.g., Altschul et al. (1990) J. Mol. Biol. 215: 403 410 and (1997)Nucleic Acids Res. 25:3389 402).

In certain embodiments, the antibody or antibody fragment for use in themethod of the invention may be mono-specific, bi-specific, ormulti-specific. Multi-specific antibodies may be specific for differentepitopes of one target polypeptide or may contain antigen-bindingdomains specific for epitopes of more than one target polypeptide. Anexemplary bi-specific antibody format that can be used in the context ofthe present invention involves the use of a first immunoglobulin (Ig)C_(H)3 domain and a second Ig C_(H)3 domain, wherein the first andsecond Ig C_(H)3 domains differ from one another by at least one aminoacid, and wherein at least one amino acid difference reduces binding ofthe bi-specific antibody to Protein A as compared to a bi-specificantibody lacking the amino acid difference. In one embodiment, the firstIg C_(H)3 domain binds Protein A and the second Ig C_(H)3 domaincontains a mutation that reduces or abolishes Protein A binding such asan H95R modification (by IMGT exon numbering; H435R by EU numbering).The second C_(H)3 may further comprise an Y96F modification (by IMGT;Y436F by EU). Further modifications that may be found within the secondC_(H)3 include: D16E, L18M, N44S, K52N, V57M, and V82I (by IMGT; D356E,L358M, N384S, K392N, V397M, and V422I by EU) in the case of lgG1 mAbs;N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the caseof lgG2 mAbs; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT;Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU) in the caseof lgG4 mAbs. Variations on the bi-specific antibody format describedabove are contemplated within the scope of the present invention.

By the phrase “therapeutically effective amount” is meant an amount thatproduces the desired effect for which it is administered. The exactamount will depend on the purpose of the treatment, and will beascertainable by one skilled in the art using known techniques (see, forexample, Lloyd (1999) The Art, Science and Technology of PharmaceuticalCompounding).

An “immunogenic composition” relates to a composition containing anantigen/immunogen, e.g. a microorganism, such as a virus or a bacterium,or a component thereof, a protein, a polypeptide, a fragment of aprotein or polypeptide, a whole cell inactivated, subunit or attenuatedvirus, or a polysaccharide, or combination thereof, administered tostimulate the recipient's humoral and/or cellular immune systems to oneor more of the antigens/immunogens present in the immunogeniccomposition. The immunogenic compositions of the present invention canbe used to treat a human susceptible to RSV and/or HMPV infection orsuspected of having or being susceptible to RSV and/or HMPV infection,by means of administering the immunogenic compositions via a systemicroute. These administrations can include injection via the intramuscular(i.m.), intradermal (i.d.), intranasal or inhalation route, orsubcutaneous (s.c.) routes; application by a patch or other transdermaldelivery device. In one embodiment, the immunogenic composition may beused in the manufacture of a vaccine or in the elicitation of polyclonalor monoclonal antibodies that could be used to passively protect ortreat a mammal.

The terms “vaccine” or “vaccine composition”, which are usedinterchangeably, refer to a composition comprising at least oneimmunogenic composition that induces an immune response in an animal.

In certain embodiments, a protein of interest comprises an antigen. Theterms “antigen,” “immunogen,” “antigenic,” “immunogenic,” “antigenicallyactive,” and “immunologically active” when made in reference to amolecule, refer to any substance that is capable of inducing a specifichumoral and/or cell-mediated immune response. In one embodiment, theantigen comprises an epitope, as defined above.

“Immunologically protective amount”, as used herein, is an amount of anantigen effective to induce an immunogenic response in the recipientthat is adequate to prevent or ameliorate signs or symptoms of disease,including adverse health effects or complications thereof. Eitherhumoral immunity or cell-mediated immunity or both can be induced. Theimmunogenic response of an animal to a composition can be evaluated,e.g., indirectly through measurement of antibody titers, lymphocyteproliferation assays, or directly through monitoring signs and symptomsafter challenge with the microorganism. The protective immunityconferred by an immunogenic composition or vaccine can be evaluated bymeasuring, e.g., reduction of shed of challenge organisms, reduction inclinical signs such as mortality, morbidity, temperature, and overallphysical condition, health and performance of the subject. The immuneresponse can comprise, without limitation, induction of cellular and/orhumoral immunity. The amount of a composition or vaccine that istherapeutically effective can vary, depending on the particular organismused, or the condition of the animal being treated or vaccinated.

An “immune response”, or “immunological response” as used herein, in asubject refers to the development of a humoral immune response, acellular-immune response, or a humoral and a cellular immune response toan antigen/immunogen. A “humoral immune response” refers to one that isat least in part mediated by antibodies. A “cellular immune response” isone mediated by T-lymphocytes or other white blood ceils or both, andincludes the production of cytokines, chemokines and similar moleculesproduced by activated T-cells, white blood ceils, or both. Immuneresponses can be determined using standard immunoassays andneutralization assays, which are known in the art.

“Immunogenicity”, as used herein, refers to the capability of a proteinor polypeptide to elicit an immune response directed specificallyagainst a bacteria or virus that causes the identified disease.

Unless specifically indicated otherwise, the term “antibody,” as usedherein, shall be understood to encompass antibody molecules comprisingtwo immunoglobulin heavy chains and two immunoglobulin light chains(i.e., “full antibody molecules”) as well as antigen-binding fragmentsthereof. The terms “antigen-binding portion” of an antibody,“antigen-binding fragment” of an antibody, and the like, as used herein,include any naturally occurring, enzymatically obtainable, synthetic, orgenetically engineered polypeptide or glycoprotein that specificallybinds an antigen to form a complex.

Preparation of Human Antibodies

As disclosed herein, anti-RSV and or anti-RSV/anti-HMPF crossneutralizing antibodies by be obtained through B cell sorting techniquesavailable to the artisan, and, for example, as described in the EXAMPLESbelow. Methods for generating human antibodies in transgenic mice arealso known in the art and may be employed in order to derive antibodiesin accordance with the present disclosure. Any such known methods can beused in the context of the present invention to make human antibodiesthat specifically bind to RSV-F (see, for example, U.S. Pat. No.6,596,541).

In certain embodiments, the antibodies of the instant invention possessaffinities (K_(D)) ranging from about 1.0×10-⁷M to about 1.0×10⁻¹²M,when measured by binding to antigen either immobilized on solid phase orin solution phase. In certain embodiments, the antibodies of theinvention possess affinities (K_(D)) ranging from about 1×10⁻⁷ M toabout 6×10⁻¹⁰M, when measured by binding to antigen either immobilizedon solid phase or in solution phase. In certain embodiments, theantibodies of the invention possess affinities (K_(D)) ranging fromabout 1×10⁻⁷ M to about 9×10⁻¹⁰M, when measured by binding to antigeneither immobilized on solid phase or in solution phase.

The anti-RSV-F and/or anti-HMPV antibodies and antibody fragmentsdisclosed herein encompass proteins having amino acid sequences thatvary from those of the described antibodies, but that retain the abilityto bind RSV-F. Such variant antibodies and antibody fragments compriseone or more additions, deletions, or substitutions of amino acids whencompared to parent sequence, but exhibit biological activity that isessentially equivalent to that of the described antibodies. Likewise,the antibody-encoding DNA sequences of the present invention encompasssequences that comprise one or more additions, deletions, orsubstitutions of nucleotides when compared to the disclosed sequence,but that encode an antibody or antibody fragment that is essentiallybioequivalent to an antibody or antibody fragment of the invention.

Two antigen-binding proteins, or antibodies, are consideredbioequivalent if, for example, they are pharmaceutical equivalents orpharmaceutical alternatives whose rate and extent of absorption do notshow a significant difference when administered at the same molar doseunder similar experimental conditions, either single does or multipledose. Some antibodies will be considered equivalents or pharmaceuticalalternatives if they are equivalent in the extent of their absorptionbut not in their rate of absorption and yet may be consideredbioequivalent because such differences in the rate of absorption areintentional and are reflected in the labeling, are not essential to theattainment of effective body drug concentrations on, e.g., chronic use,and are considered medically insignificant for the particular drugproduct studied.

In one embodiment, two antigen-binding proteins are bioequivalent ifthere are no clinically meaningful differences in their safety, purity,and potency.

In one embodiment, two antigen-binding proteins are bioequivalent if apatient can be switched one or more times between the reference productand the biological product without an expected increase in the risk ofadverse effects, including a clinically significant change inimmunogenicity, or diminished effectiveness, as compared to continuedtherapy without such switching.

In one embodiment, two antigen-binding proteins are bioequivalent ifthey both act by a common mechanism or mechanisms of action for thecondition or conditions of use, to the extent that such mechanisms areknown.

Bioequivalence may be demonstrated by in vivo and/or in vitro methods.Bioequivalence measures include, e.g., (a) an in vivo test in humans orother mammals, in which the concentration of the antibody or itsmetabolites is measured in blood, plasma, serum, or other biologicalfluid as a function of time; (b) an in vitro test that has beencorrelated with and is reasonably predictive of human in vivobioavailability data; (c) an in vivo test in humans or other mammals inwhich the appropriate acute pharmacological effect of the antibody (orits target) is measured as a function of time; and (d) in awell-controlled clinical trial that establishes safety, efficacy, orbioavailability or bioequivalence of an antibody.

Bioequivalent variants of the antibodies of the invention may beconstructed by, for example, making various substitutions of residues orsequences or deleting terminal or internal residues or sequences notneeded for biological activity. For example, cysteine residues notessential for biological activity can be deleted or replaced with otheramino acids to prevent formation of unnecessary or incorrectintramolecular disulfide bridges upon renaturation. In other contexts,bioequivalent antibodies may include antibody variants comprising aminoacid changes, which modify the glycosylation characteristics of theantibodies, e.g., mutations that eliminate or remove glycosylation.

Biological and Biophysical Characteristics of the Antibodies

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof specifically bind to Respiratory Syncytial Virus (RSV)F protein (F), wherein at least one of the CDRH1, CDRH2, CDRH3, CDRL1,CDRL2, and/or CDRL3 amino acid sequences of such antibody or theantigen-binding fragment thereof is at least 70% identical; at least 75%identical; 80% identical; at least 85% identical; at least 90%identical; at least 95% identical; at least 96% identical; at least 97%identical; at least 98% identical; at least 99%; and/or all percentagesof identity in between; to at least one of the CDRH1, a CDRH2, a CDRH3,a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed inTable 6 of an antibody selected from Antibody Number 232 throughAntibody Number 372 as disclosed in Table 6. In certain embodiments,such antibodies also possess at least one, two, three, four, five, six,seven, eight, nine, ten, or more characteristics disclosed in theimmediately following eleven paragraphs.

Without wishing to be bound by any theory, it is believed that theinventive antibodies and antigen-binding fragments thereof may functionby binding to RSV-F, preferably in the PreF conformation, and in sodoing act to block the fusion of the viral membrane with the host cellmembrane. The antibodies of the present invention may also function bybinding to RSV-F and in so doing block the cell to cell spread of thevirus and block syncytia formation associated with RSV infection ofcells. Advantageously, both RSV subtype A and RSV subtype B areeffectively blocked, or neutralized, by the majority of the anti-RSVantibodies disclosed herein.

In certain embodiments, the inventive antibodies and antigen-bindingfragment thereof display better binding affinity for the PreF form ofRSV-F relative to the PostF form of RSV-F.

In certain other embodiments, the inventive antibodies andantigen-binding fragments thereof advantageously display a clean or lowpolyreactivity profile (see, e.g., WO 2014/179363 and Xu et al., ProteinEng Des Sel, October; 26(10):663-70. doi: 10.1093/protein/gzt047), andare thus particularly amenable to development as safe, efficacious, anddevelopable therapeutic and/or prophylactic anti-RSV and/or HMPVtreatments.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof, without wishing to be bound by any theory, mayfunction by blocking or inhibiting RSV fusion to the cell membrane bybinding to any one or more of, e.g., antigenic Sites Ø, I, II, III, IV,or Site V of the PreF conformation of the F protein. In certainembodiments, the inventive antibodies display antigenic site specificityfor Site Ø, Site V, or Site III of PreF relative to RSV-F Site I, SiteII, or Site IV.

In certain embodiments, at least a portion of the epitope with which theinventive antibodies and antigen-binding fragments thereof interactscomprises a portion of the α3 helix and β3/β4 hairpin of PreF. Incertain embodiments, substantially all of the epitope of such antibodiescomprises the α3 helix and β3/β4 hairpin of PreF. In still furtherembodiments, the inventive antibodies corss-copmpete with antibodiesthat recognize a portion or substantially all of the α3 helix and β3/β4hairpin of PreF.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof display an in vitro neutralization potency (IC₅₀) ofbetween about 0.5 microgram/milliliter (ug/ml) to about 5 ug/ml; betweenabout 0.05 ug/ml to about 0.5 ug/ml; or less than about 0.05 mg/ml.

In certain embodiments, the binding affinity and/or epitopic specificityof the inventive antibodies and antigen-binding fragments thereof forany one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9,and DG in FIG. 7A is reduced or eliminated relative to the bindingaffinity and/or epitopic specificity of said antibody or antigen-bindingfragment thereof for the RSV-F or RSV-F DS-Cav1.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof display a cross-neutralization potency (IC₅₀) againsthuman metapneumovirus (HMPV) as well as RSV. In certain suchembodiments, the inventive antibodies and antigen-binding fragmentsthereof comprise at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2,and/or CDRL3 amino acid sequences of such antibody or theantigen-binding fragment thereof is at least 70% identical; at least 75%identical; 80% identical; at least 85% identical; at least 90%identical; at least 95% identical; at least 96% identical; at least 97%identical; at least 98% identical; at least 99%; and/or all percentagesof identity in between; to at least one of the CDRH1, a CDRH2, a CDRH3,a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed inTable 6 of Antibody Number 340 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof do not complete with D25, MPE8, palivisumab,motavizumab, or AM-14. In certain embodiments, the inventive antibodiesand antigen-binding fragments thereof do not complete with D25, MPE8,palivisumab, or motavizumab. In certain embodiments, the inventiveantibodies and antigen-binding fragments thereof do not complete withMPE8, palivisumab, or motavizumab. In certain embodiments, the inventiveantibodies and antigen-binding fragments thereof do not complete withD25, palivisumab, or motavizumab. In certain embodiments, the inventiveantibodies and antigen-binding fragments thereof do not complete withD25. In certain embodiments, the inventive antibodies andantigen-binding fragments thereof do not complete with MPE8. In certainembodiments, the inventive antibodies and antigen-binding fragmentsthereof do not complete with palivisumab. In certain embodiments, theinventive antibodies and antigen-binding fragments thereof do notcomplete with motavizumab.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof complete with one or more of D25, MPE8, palivisumab,motavizumab, and/or AM-14.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof display at least about 2-fold; at least about 3-fold;at least about 4-fold; at least about 5-fold; at least about 6-fold; atleast about 7-fold; at least about 8-fold; at least about 9-fold; atleast about 10-fold; at least about 15-fold; at least about 20-fold; atleast about 25-fold; at least about 30-fold; at least about 35-fold; atleast about 40-fold; at least about 50-fold; at least about 55-fold; atleast about 60-fold; at least about 70-fold; at least about 80-fold; atleast about 90-fold; at least about 100-fold; greater than about100-fold; and folds in between any of the foregoing; greaterneutralization potency (IC50) than D25 and/or palivizumab.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof comprise the CDRH3 amino acid sequence of any one ofthe antibodies designated Antibody Number 232 through Antibody Number372 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof comprise the CDRH2 amino acid sequence of any one ofthe antibodies designated Antibody Number 232 through Antibody Number372 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof comprise the CDRH1 amino acid sequence of any one ofthe antibodies designated Antibody Number 232 through Antibody Number372 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof comprise the CDRL3 amino acid sequence of any one ofthe antibodies designated Antibody Number 232 through Antibody Number372 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof comprise the CDRL2 amino acid sequence of any one ofthe antibodies designated Antibody Number 232 through Antibody Number372 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof comprise the CDRL1 amino acid sequence of any one ofthe antibodies designated Antibody Number 232 through Antibody Number372 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof comprise any combination of two, three, four, five, orsix characteristics disclosed in the immediately preceeding sixparagraphs.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof comprise a heavy chain (HC) amino acid sequence of anyone of the antibodies designated Antibody Number 232 through AntibodyNumber 372 as disclosed in Table 6. In certain embodiments, theinventive antibodies and antigen-binding fragments thereof comprise alight chain (LC) amino acid sequence of any one of the antibodiesdesignated Antibody Number 232 through Antibody Number 372 as disclosedin Table 6. In certain embodiments, the inventive antibodies andantigen-binding fragments thereof comprise a heavy chain (HC) amino acidsequence and a light chain (LC) amino acid sequence of any one of theantibodies designated Antibody Number 232 through Antibody Number 372 asdisclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof are each selected from the group consisting antibodiesthat are at least 70% identical; at least 75% identical; 80% identical;at least 85% identical; at least 90% identical; at least 95% identical;at least 96% identical; at least 97% identical; at least 98% identical;at least 99%; and/or all percentages of identity in between; to any oneof the antibodies designated as Antibody Number 232 through AntibodyNumber 372 as disclosed in Table 6.

In certain embodiments, the inventive antibodies and antigen-bindingfragments thereof comprise are each selected from the group consistingof the antibodies designated as Antibody Number 232 through AntibodyNumber 372 as disclosed in Table 6.

In certain embodiments, isolated nucleic acid sequences are providedthat encode antibodies that specifically bind to Respiratory SyncytialVirus (RSV) F protein and antigen-binding fragments thereof, wherein atleast one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 aminoacid sequences of the antibody or the antigen-binding fragment thereofis at least 70% identical; at least 75% identical; 80% identical; atleast 85% identical; at least 90% identical; at least 95% identical; atleast 96% identical; at least 97% identical; at least 98% identical; atleast 99%; and/or all percentages of identity in between; to at leastone the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acidsequences as disclosed in Table 6 of an antibody selected from AntibodyNumber 232 through Antibody Number 372 as disclosed in Table 6. Incertain embodiments, such nucleic acid sequences are selected from thosenucleic acid sequences that are disclosed in Table 6, and complimentsthereof.

In certain embodiments, isolated nucleic acid sequences are providedthat encode the inventive antibodies and antigen-binding fragmentsthereof, wherein such nucleic acid sequences comprise sequences thatencode the CDRH3 amino acid sequence of the antibodies designatedAntibody Number 232 through Antibody Number 372 as disclosed in Table 6.In certain embodiments, such nucleic acid sequences are selected fromthose nucleic acid sequences that are disclosed in Table 6, andcompliments thereof.

In certain embodiments, isolated nucleic acid sequences are providedthat encode the inventive antibodies and antigen-binding fragmentsthereof, wherein such nucleic acid sequences comprise sequences thatencode the CDRH2 amino acid sequences of the antibodies designatedAntibody Number 232 through Antibody Number 372 as disclosed in Table 6.In certain embodiments, such nucleic acid sequences are selected fromthose nucleic acid sequences that are disclosed in Table 6, andcompliments thereof.

In certain embodiments, isolated nucleic acid sequences are providedthat encode the inventive antibodies and antigen-binding fragmentsthereof, wherein such nucleic acid sequences comprise sequences thatencode the CDRH1 amino acid sequences of the antibodies designatedAntibody Number 232 through Antibody Number 372 as disclosed in Table 6.In certain embodiments, such nucleic acid sequences are selected fromthose nucleic acid sequences that are disclosed in Table 6, andcompliments thereof.

In certain embodiments, isolated nucleic acid sequences are providedthat encode the inventive antibodies and antigen-binding fragmentsthereof, wherein such nucleic acid sequences comprise sequences thatencode the CDRL3 amino acid sequences of the antibodies designatedAntibody Number 232 through Antibody Number 372 as disclosed in Table 6.In certain embodiments, such nucleic acid sequences are selected fromthose nucleic acid sequences that are disclosed in Table 6, andcompliments thereof.

In certain embodiments, isolated nucleic acid sequences are providedthat encode the inventive antibodies and antigen-binding fragmentsthereof, wherein such nucleic acid sequences comprise sequences thatencode the CDRL2 amino acid sequences of the antibodies designatedAntibody Number 232 through Antibody Number 372 as disclosed in Table 6.In certain embodiments, such nucleic acid sequences are selected fromthose nucleic acid sequences that are disclosed in Table 6, andcompliments thereof.

In certain embodiments, isolated nucleic acid sequences are providedthat encode the inventive antibodies and antigen-binding fragmentsthereof, wherein such nucleic acid sequences comprise sequences thatencode the CDRL1 amino acid sequences of the antibodies designatedAntibody Number 232 through Antibody Number 372 as disclosed in Table 6.In certain embodiments, such nucleic acid sequences are selected fromthose nucleic acid sequences that are disclosed in Table 6, andcompliments thereof.

In certain embodiments, isolated nucleic acid sequences are providedthat encode the inventive antibodies and antigen-binding fragmentsthereof, wherein such nucleic acid sequences comprise sequences thatencode the heavy chain (HC) amino acid sequences of the antibodiesdesignated Antibody Number 232 through Antibody Number 372 as disclosedin Table 6. In certain embodiments, such nucleic acid sequences areselected from those nucleic acid sequences that are disclosed in Table6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are providedthat encode the inventive antibodies and antigen-binding fragmentsthereof, wherein such nucleic acid sequences comprise sequences thatencode the heavy chain (LC) amino acid sequences of the antibodiesdesignated Antibody Number 232 through Antibody Number 372 as disclosedin Table 6. In certain embodiments, such nucleic acid sequences areselected from those nucleic acid sequences that are disclosed in Table6, and compliments thereof.

In certain embodiments, isolated nucleic acid sequences are providedthat encode the inventive antibodies and antigen-binding fragmentsthereof, wherein such nucleic acid sequences comprise sequences are eachselected from the group consisting of sequences that are at least 70%identical; at least 75% identical; 80% identical; at least 85%identical; at least 90% identical; at least 95% identical; at least 96%identical; at least 97% identical; at least 98% identical; at least 99%;and/or all percentages of identity in between; to any one of the nucleicacid sequences that are disclosed in Table 6, and compliments thereof.

In certain embodiments, expression vectors are provided comprising theisolated nucleic acid sequences disclose herein and throughout, and inparticular in the immediately preceeding ten paragraphs.

In certain embodiments, host cells transfected, transformed, ortransduced with the nucleic acid sequences and/or the expression vectorsdisclosed immediately above are provided.

Epitope Mapping and Related Technologies

As described above and as demonstrated in the EXAMPLES, Applicants havecharacterized the epitopic specificities, bin assignments, and antigenicsite assignments of the inventive antibodies and antigen-bindingfragments thereof. In addition to the methods for conducting suchcharacterization, various other techniques are available to the artisanthat can be used to carry out such characterization or to otherwiseascertain whether an antibody “interacts with one or more amino acids”within a polypeptide or protein. Exemplary techniques include, forexample, a routine cross-blocking assay such as that describedAntibodies, Harlow and Lane (Cold Spring Harbor Press, Cold SpringHarb., NY) can be performed. Other methods include alanine scanningmutational analysis, peptide blot analysis (Reineke (2004) Methods MolBiol 248:443-63), peptide cleavage analysis crystallographic studies andNMR analysis. In addition, methods such as epitope excision, epitopeextraction and chemical modification of antigens can be employed (Tomer(2000) Protein Science 9: 487-496). Another method that can be used toidentify the amino acids within a polypeptide with which an antibodyinteracts is hydrogen/deuterium exchange detected by mass spectrometry.In general terms, the hydrogen/deuterium exchange method involvesdeuterium-labeling the protein of interest, followed by binding theantibody to the deuterium-labeled protein. Next, the protein/antibodycomplex is transferred to water and exchangeable protons within aminoacids that are protected by the antibody complex undergodeuterium-to-hydrogen back-exchange at a slower rate than exchangeableprotons within amino acids that are not part of the interface. As aresult, amino acids that form part of the protein/antibody interface mayretain deuterium and therefore exhibit relatively higher mass comparedto amino acids not included in the interface. After dissociation of theantibody, the target protein is subjected to protease cleavage and massspectrometry analysis, thereby revealing the deuterium-labeled residuesthat correspond to the specific amino acids with which the antibodyinteracts. See, e.g., Ehring (1999) Analytical Biochemistry 267{2):252-259; Engen and Smith (2001) Anal. Chem. 73:256A-265A.

As the artisan will understand, an epitope can be formed both fromcontiguous amino acids or noncontiguous amino acids juxtaposed bytertiary folding of a protein. Epitopes formed from contiguous aminoacids are typically retained on exposure to denaturing solvents, whereasepitopes formed by tertiary folding are typically lost on treatment withdenaturing solvents. An epitope typically includes at least 3, and moreusually, at least 5 or 8-10 amino acids in a unique spatialconformation.

Modification-Assisted Profiling (MAP), also known as AntigenStructure-based Antibody Profiling (ASAP) is a method that categorizeslarge numbers of monoclonal antibodies (mAbs) directed against the sameantigen according to the similarities of the binding profile of eachantibody to chemically or enzymatically modified antigen surfaces (US2004/0101920). Each category may reflect a unique epitope eitherdistinctly different from or partially overlapping with epitoperepresented by another category. This technology allows rapid filteringof genetically identical antibodies, such that characterization can befocused on genetically distinct antibodies. When applied to hybridomascreening, MAP may facilitate identification of rare hybridoma clonesthat produce mAbs having the desired characteristics. MAP may be used tosort the antibodies of the invention into groups of antibodies bindingdifferent epitopes.

In certain embodiments, the inventive antibodies and/or antigen-bindingfragments thereof interact with an amino acid sequence comprising theamino acid residues that are altered in one or more of the F proteinpatch variants disclosed, e.g., in the EXAMPLES and which are depictedin, e.g., FIG. 7A and which are designated as RSV F Variants 1, 2, 3, 4,5, 6, 7, 8, 9, and DG. In certain embodiments, such inventive antibodiesand antigen-binding fragments thereof interact with an amino acidsequence comprising the amino acid residues that are altered in RSV FVariant 2. In certain embodiments, the inventive antibodies and/orantigen-binding fragments thereof interact with amino acid residues thatextend beyond the region(s) identified above by about 5 to 10 amino acidresidues, or by about 10 to 15 amino acid residues, or by about 15 to 20amino acid residues towards either the amino terminal or the carboxyterminal of the RSV-F protein.

In certain embodiments, the antibodies of the present invention do notbind to the same epitope on RSV-F protein as palivizumab, motavizumab,MPE8, or AM-14.

As the artisan understands, one can easily determine whether an antibodybinds to the same epitope as, or competes for binding with, a referenceanti-RSV-F antibody by using routine methods available in the art. Forexample, to determine if a test antibody binds to the same epitope as areference RSV-F antibody of the invention, the reference antibody isallowed to bind to a RSV-F protein or peptide under saturatingconditions. Next, the ability of a test antibody to bind to the RSV-Fmolecule is assessed. If the test antibody is able to bind to RSV-Ffollowing saturation binding with the reference anti-RSV-F antibody, itcan be concluded that the test antibody binds to a different epitopethan the reference anti-RSV-F antibody. On the other hand, if the testantibody is not able to bind to the RSV-F molecule following saturationbinding with the reference anti-RSV-F antibody, then the test antibodymay bind to the same epitope as the epitope bound by the referenceanti-RSV-F antibody of the invention.

To determine if an antibody competes for binding with a referenceanti-RSV-F antibody, the above-described binding methodology isperformed in two orientations: In a first orientation, the referenceantibody is allowed to bind to a RSV-F molecule under saturatingconditions followed by assessment of binding of the test antibody to theRSV-F molecule. In a second orientation, the test antibody is allowed tobind to a RSV-F molecule under saturating conditions followed byassessment of binding of the reference antibody to the RSV-F molecule.If, in both orientations, only the first (saturating) antibody iscapable of binding to the RSV-F molecule, then it is concluded that thetest antibody and the reference antibody compete for binding to RSV-F.As will be appreciated by a person of ordinary skill in the art, anantibody that competes for binding with a reference antibody may notnecessarily bind to the identical epitope as the reference antibody, butmay sterically block binding of the reference antibody by binding anoverlapping or adjacent epitope.

Two antibodies bind to the same or overlapping epitope if eachcompetitively inhibits (blocks) binding of the other to the antigen.That is, a 1-, 5-, 10-, 20- or 100-fold excess of one antibody inhibitsbinding of the other by at least 50% but preferably 75%, 90% or even 99%as measured in a competitive binding assay (see, e.g., Junghans et al.,Cancer Res. (1990) 50:1495-1502). Alternatively, two antibodies have thesame epitope if essentially all amino acid mutations in the antigen thatreduce or eliminate binding of one antibody reduce or eliminate bindingof the other. Two antibodies have overlapping epitopes if some aminoacid mutations that reduce or eliminate binding of one antibody reduceor eliminate binding of the other.

Additional routine experimentation (e.g., peptide mutation and bindinganalyses) can then be carried out to confirm whether the observed lackof binding of the test antibody is in fact due to binding to the sameepitope as the reference antibody or if steric blocking (or anotherphenomenon) is responsible for the lack of observed binding. Experimentsof this sort can be performed using ELISA, RIA, surface plasmonresonance, flow cytometry or any other quantitative or qualitativeantibody-binding assay available in the art.

Immunoconjugates

The invention encompasses a human RSV-F monoclonal antibody conjugatedto a therapeutic moiety (“immunoconjugate”), such as an agent that iscapable of reducing the severity of primary infection with RSV and/orHMPV, or to ameliorate at least one symptom associated with RSVinfection and/or HMPV infection, including coughing, fever, pneumonia,or the severity thereof. Such an agent may be a second differentantibody to RSV-F and/or HMPV, or a vaccine. The type of therapeuticmoiety that may be conjugated to the anti-RSV-F antibody and/oranti-HMPV antibody and will take into account the condition to betreated and the desired therapeutic effect to be achieved.Alternatively, if the desired therapeutic effect is to treat thesequelae or symptoms associated with RSV and/or HMPV infection, or anyother condition resulting from such infection, such as, but not limitedto, pneumonia, it may be advantageous to conjugate an agent appropriateto treat the sequelae or symptoms of the condition, or to alleviate anyside effects of the antibodies of the invention. Examples of suitableagents for forming immunoconjugates are known in the art, see forexample, WO 05/103081.

Multi-Specific Antibodies

The antibodies of the present invention may be mono-specific,bi-specific, or multi-specific. Multi-specific antibodies may bespecific for different epitopes of one target polypeptide or may containantigen-binding domains specific for more than one target polypeptide.See, e.g., Tutt et al., 1991, J. Immunol. 147:60-69; Kufer et al., 2004,Trends Biotechnol. 22:238-244. The antibodies of the present inventioncan be linked to or co-expressed with another functional molecule, e.g.,another peptide or protein. For example, an antibody or fragment thereofcan be functionally linked {e.g., by chemical coupling, genetic fusion,noncovalent association or otherwise) to one or more other molecularentities, such as another antibody or antibody fragment to produce abi-specific or a multi-specific antibody with a second bindingspecificity.

An exemplary bi-specific antibody format that can be used in the contextof the present invention involves the use of a first immunoglobulin (Ig)C_(H)3 domain and a second Ig C_(H)3 domain, wherein the first andsecond Ig C_(H)3 domains differ from one another by at least one aminoacid, and wherein at least one amino acid difference reduces binding ofthe bi-specific antibody to Protein A as compared to a bi-specificantibody lacking the amino acid difference. In one embodiment, the firstIg C_(H)3 domain binds Protein A and the second Ig C_(H)3 domaincontains a mutation that reduces or abolishes Protein A binding such asan H95R modification (by IMGT exon numbering; H435R by EU numbering).The second C_(H)3 may further comprise a Y96F modification (by IMGT;Y436F by EU). Further modifications that may be found within the secondC_(H)3 include: D16E, L18M, N44S, K52N, V57M, and V82I (by IMGT; D356E,L358M, N384S, K392N, V397M, and V422I by EU) in the case of lgG1antibodies; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU)in the case of lgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q,and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422Iby EU) in the case of lgG4 antibodies. Variations on the bi-specificantibody format described above are contemplated within the scope of thepresent invention.

Therapeutic Administration and Formulations

The invention provides therapeutic compositions comprising the inventiveanti-RSV-F antibodies or antigen-binding fragments thereof. Theadministration of therapeutic compositions in accordance with theinvention will be administered with suitable carriers, excipients, andother agents that are incorporated into formulations to provide improvedtransfer, delivery, tolerance, and the like. A multitude of appropriateformulations can be found in the formulary known to all pharmaceuticalchemists: Remington's Pharmaceutical Sciences, Mack Publishing Company,Easton, Pa. These formulations include, for example, powders, pastes,ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrousabsorption pastes, oil-in-water and water-in-oil emulsions, emulsionscarbowax (polyethylene glycols of various molecular weights), semi-solidgels, and semi-solid mixtures containing carbowax. See also Powell etal. “Compendium of excipients for parenteral formulations” PDA (1998) JPharm Sci Technol 52:238-31 1.

The dose of each of the antibodies of the invention may vary dependingupon the age and the size of a subject to be administered, targetdisease, conditions, route of administration, and the like. When theantibodies of the present invention are used for treating a RSVinfection and/or HMPV infection in a patient, or for treating one ormore symptoms associated with a RSV infection and/or HMPV infection,such as the cough or pneumonia associated with a RSV infection and/orHMPV in a patient, or for lessening the severity of the disease, it isadvantageous to administer each of the antibodies of the presentinvention intravenously or subcutaneously normally at a single dose ofabout 0.01 to about 30 mg/kg body weight, more preferably about 0.1 toabout 20 mg/kg body weight, or about 0.1 to about 15 mg/kg body weight,or about 0.02 to about 7 mg/kg body weight, about 0.03 to about 5 mg/kgbody weight, or about 0.05 to about 3 mg/kg body weight, or about 1mg/kg body weight, or about 3.0 mg/kg body weight, or about 10 mg/kgbody weight, or about 20 mg/kg body weight. Multiple doses may beadministered as necessary. Depending on the severity of the condition,the frequency and the duration of the treatment can be adjusted. Incertain embodiments, the antibodies or antigen-binding fragments thereofof the invention can be administered as an initial dose of at leastabout 0.1 mg to about 800 mg, about 1 to about 600 mg, about 5 to about300 mg, or about 10 to about 150 mg, to about 100 mg, or to about 50 mg.In certain embodiments, the initial dose may be followed byadministration of a second or a plurality of subsequent doses of theantibodies or antigen-binding fragments thereof in an amount that can beapproximately the same or less than that of the initial dose, whereinthe subsequent doses are separated by at least 1 day to 3 days; at leastone week, at least 2 weeks; at least 3 weeks; at least 4 weeks; at least5 weeks; at least 6 weeks; at least 7 weeks; at least 8 weeks; at least9 weeks; at least 10 weeks; at least 12 weeks; or at least 14 weeks.

Various delivery systems are known and can be used to administer thepharmaceutical composition of the invention, e.g., encapsulation inliposomes, microparticles, microcapsules, recombinant cells capable ofexpressing the mutant viruses, receptor mediated endocytosis (see, e.g.,Wu et al. (1987) J. Biol. Chem. 262:4429-4432). Methods of introductioninclude, but are not limited to, intradermal, transdermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural and oral routes. The composition may be administered by anyconvenient route, for example by infusion or bolus injection, byabsorption through epithelial or mucocutaneous linings {e.g., oralmucosa, nasal mucosa, rectal and intestinal mucosa, etc.) and may beadministered together with other biologically active agents.Administration can be systemic or local. It may be delivered as anaerosolized formulation (See US2011/0311515 and US2012/0128669). Thedelivery of agents useful for treating respiratory diseases byinhalation is becoming more widely accepted (See A. J. Bitonti and J. A.Dumont, (2006), Adv. Drug Deliv. Rev, 58:1 106-1 1 18). In addition tobeing effective at treating local pulmonary disease, such a deliverymechanism may also be useful for systemic delivery of antibodies (SeeMaillet et al. (2008), Pharmaceutical Research, Vol. 25, No. 6, 2008).

The pharmaceutical composition can be also delivered in a vesicle, inparticular a liposome (see, for example, Langer (1990) Science249:1527-1533).

In certain situations, the pharmaceutical composition can be deliveredin a controlled release system. In one embodiment, a pump may be used.In another embodiment, polymeric materials can be used. In yet anotherembodiment, a controlled release system can be placed in proximity ofthe composition's target, thus requiring only a fraction of the systemicdose.

The injectable preparations may include dosage forms for intravenous,subcutaneous, intracutaneous and intramuscular injections, dripinfusions, etc. These injectable preparations may be prepared by methodspublicly known. For example, the injectable preparations may beprepared, e.g., by dissolving, suspending or emulsifying the antibody orits salt described above in a sterile aqueous medium or an oily mediumconventionally used for injections. As the aqueous medium forinjections, there are, for example, physiological saline, an isotonicsolution containing glucose and other auxiliary agents, etc., which maybe used in combination with an appropriate solubilizing agent such as analcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol,polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80,HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)],etc. As the oily medium, there are employed, e.g., sesame oil, soybeanoil, etc., which may be used in combination with a solubilizing agentsuch as benzyl benzoate, benzyl alcohol, etc. The injection thusprepared is preferably filled in an appropriate ampoule.

A pharmaceutical composition of the present invention can be deliveredsubcutaneously or intravenously with a standard needle and syringe. Inaddition, with respect to subcutaneous delivery, a pen delivery devicereadily has applications in delivering a pharmaceutical composition ofthe present invention. Such a pen delivery device can be reusable ordisposable. A reusable pen delivery device generally utilizes areplaceable cartridge that contains a pharmaceutical composition. Onceall of the pharmaceutical composition within the cartridge has beenadministered and the cartridge is empty, the empty cartridge can readilybe discarded and replaced with a new cartridge that contains thepharmaceutical composition. The pen delivery device can then be reused.In a disposable pen delivery device, there is no replaceable cartridge.Rather, the disposable pen delivery device comes prefilled with thepharmaceutical composition held in a reservoir within the device. Oncethe reservoir is emptied of the pharmaceutical composition, the entiredevice is discarded.

Numerous reusable pen and autoinjector delivery devices haveapplications in the subcutaneous delivery of a pharmaceuticalcomposition of the present invention. Examples include, but certainlyare not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK),DISETRONIC™ pen (Disetronic Medical Systems, Burghdorf, Switzerland),HUMALOG MIX 75/25™ pen, HUMALOG™ pen, HUMALIN 70/30™ pen (Eli Lilly andCo., Indianapolis, Ind.), NOVOPEN™ I, II and III (Novo Nordisk,Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen,Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, N.J.), OPTIPEN™,OPTIPEN PRO™ OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt,Germany), to name only a few. Examples of disposable pen deliverydevices having applications in subcutaneous delivery of a pharmaceuticalcomposition of the present invention include, but certainly are notlimited to the SOLOSTAR™ pen (sanofi-aventis), the FLEXPEN™ (NovoNordisk), and the KWIKPEN™ (Eli Lilly), the SURECLICK™ Autoinjector(Amgen, Thousands Oaks, Calif.), the PENLET™ (Haselmeier, Stuttgart,Germany), the EPIPEN (Dey, L.P.) and the HUMIRA™ Pen (Abbott Labs,Abbott Park, Ill.), to name only a few.

Advantageously, the pharmaceutical compositions for oral or parenteraluse described above are prepared into dosage forms in a unit dose suitedto fit a dose of the active ingredients. Such dosage forms in a unitdose include, for example, tablets, pills, capsules, injections(ampoules), suppositories, etc. The amount of the aforesaid antibodycontained is generally about 5 to about 500 mg per dosage form in a unitdose; especially in the form of injection, it is preferred that theaforesaid antibody is contained in about 5 to about 100 mg and in about10 to about 250 mg for the other dosage forms.

Administration Regimens

According to certain embodiments, multiple doses of an antibody to RSV-Fand/or HMPV may be administered to a subject over a defined time course.The methods according to this aspect of the invention comprisesequentially administering to a subject multiple doses of an antibody toRSV-F and/or HMPV. As used herein, “sequentially administering” meansthat each dose of antibody to RSV-F and/or HMPV is administered to thesubject at a different point in time, e.g., on different days separatedby a predetermined interval (e.g., hours, days, weeks or months). Thepresent invention includes methods which comprise sequentiallyadministering to the patient a single initial dose of an antibody toRSV-F and/or HMPV, followed by one or more secondary doses of theantibody to RSV-F and/or HMPV and optionally followed by one or moretertiary doses of the antibody to RSV-F and/or HMPV.

The terms “initial dose,” “secondary doses,” and “tertiary doses,” referto the temporal sequence of administration of the antibody to RSV-Fand/or HMPV. Thus, the “initial dose” is the dose which is administeredat the beginning of the treatment regimen (also referred to as the“baseline dose”); the “secondary doses” are the doses which areadministered after the initial dose; and the “tertiary doses” are thedoses which are administered after the secondary doses. The initial,secondary, and tertiary doses may all contain the same amount ofantibody to RSV-F and/or HMPV, but generally may differ from one anotherin terms of frequency of administration. In certain embodiments,however, the amount of antibody to RSV-F and/or HMPV contained in theinitial, secondary and/or tertiary doses vary from one another (e.g.,adjusted up or down as appropriate) during the course of treatment. Incertain embodiments, two or more (e.g., 2, 3, 4, or 5) doses areadministered at the beginning of the treatment regimen as “loadingdoses” followed by subsequent doses that are administered on a lessfrequent basis (e.g., “maintenance doses”).

In one exemplary embodiment of the present invention, each secondaryand/or tertiary dose is administered 1 to 26 (e.g., 1, 1½, 2, 2½, 3, 3½,4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12½, 13,13½, 14, 14½, 15, 15½, 16, 16½, 17, 17½, 18, 18½, 19, 19½, 20, 20½, 21,21½, 22, 22½, 23, 23½, 24, 24½, 25, 25½, 26, 26½, or more) weeks afterthe immediately preceding dose. The phrase “the immediately precedingdose,” as used herein, means, in a sequence of multiple administrations,the dose of antibody to RSV-F and/or HMPV which is administered to apatient prior to the administration of the very next dose in thesequence with no intervening doses.

The methods according to this aspect of the invention may compriseadministering to a patient any number of secondary and/or tertiary dosesof an antibody to RSV-F and/or HIMPV. For example, in certainembodiments, only a single secondary dose is administered to thepatient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8,or more) secondary doses are administered to the patient. Likewise, incertain embodiments, only a single tertiary dose is administered to thepatient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8,or more) tertiary doses are administered to the patient.

In embodiments involving multiple secondary doses, each secondary dosemay be administered at the same frequency as the other secondary doses.For example, each secondary dose may be administered to the patient 1 to2 weeks after the immediately preceding dose. Similarly, in embodimentsinvolving multiple tertiary doses, each tertiary dose may beadministered at the same frequency as the other tertiary doses. Forexample, each tertiary dose may be administered to the patient 2 to 4weeks after the immediately preceding dose. Alternatively, the frequencyat which the secondary and/or tertiary doses are administered to apatient can vary over the course of the treatment regimen. The frequencyof administration may also be adjusted during the course of treatment bya physician depending on the needs of the individual patient followingclinical examination.

Accordingly, in certain embodiments are provided pharmaceuticalcompositions comprising: one or more of the inventive antibodies orantigen-binding fragments thereof disclosed herein and throughout and apharmaceutically acceptable carrier and/or one or more excipients. Incertain other embodiments are provided pharmaceutical compositionscomprising: one or more nucleic acid sequences encoding one or moreinventive antibodies or antigen-binding fragments thereof, or one ormore the expression vectors harbouring such nucleic acid sequences; anda pharmaceutically acceptable carrier and/or one or more excipients.

Therapeutic Uses of the Antibodies

Due to their binding to and interaction with the RSV fusion protein(RSV-F), it is believe that the inventive antibodies and antigen-bindingfragments thereof are useful—without wishing to be bound to anytheory—for preventing fusion of the virus with the host cell membrane,for preventing cell to cell virus spread, and for inhibition of syncytiaformation. Additionally, as Applicants have demonstrated herein that,surprisingly, a subset of the inventive anti-RSV antibodies andantigen-binding fragment thereof display crass-neutralizing potencyagainst HMPV, the inventive antibodies and antigen-binding fragmentsthereof are advantageous for preventing an infection of a subject withRSV and/or HMPV when administered prophylactically. Alternatively, theantibodies of the present invention may be useful for ameliorating atleast one symptom associated with the infection, such as coughing,fever, pneumonia, or for lessening the severity, duration, and/orfrequency of the infection. The antibodies of the invention are alsocontemplated for prophylactic use in patients at risk for developing oracquiring an RSV infection and/or HMPV infection. These patients includepre-term infants, full term infants born during RSV season (late fall toearly spring), the elderly (for example, in anyone 65 years of age orolder) and/or HMPV season, or patients immunocompromised due to illnessor treatment with immunosuppressive therapeutics, or patients who mayhave an underlying medical condition that predisposes them to an RSVinfection (for example, cystic fibrosis patients, patients withcongestive heart failure or other cardiac conditions, patients withairway impairment, patients with COPD) and/or HMPV infection. It iscontemplated that the antibodies of the invention may be used alone, orin conjunction with a second agent, or third agent for treating RSVinfection and/or HMPV infection, or for alleviating at least one symptomor complication associated with the RSV infection and/or HMPV infection,such as the fever, coughing, bronchiolitis, or pneumonia associatedwith, or resulting from such an infection. The second or third agentsmay be delivered concurrently with the antibodies of the invention, orthey may be administered separately, either before or after theantibodies of the invention. The second or third agent may be ananti-viral such as ribavirin, an NSAID or other agents to reduce feveror pain, another second but different antibody that specifically bindsRSV-F, an agent (e.g. an antibody) that binds to another RSV antigen,such as RSV-G, a vaccine against RSV, an siRNA specific for an RSVantigen.

In yet a further embodiment of the invention the present antibodies areused for the preparation of a pharmaceutical composition for treatingpatients suffering from a RSV infection and/or HMPV infection. In yetanother embodiment of the invention the present antibodies are used forthe preparation of a pharmaceutical composition for reducing theseverity of a primary infection with RSV and/or HMPV, or for reducingthe duration of the infection, or for reducing at least one symptomassociated with the RSV infection and/or the HMPV infection. In afurther embodiment of the invention the present antibodies are used asadjunct therapy with any other agent useful for treating an RSVinfection and/or and HMPV infectin, including an antiviral, a toxoid, avaccine, a second RSV-F antibody, or any other antibody specific for anRSV antigen, including an RSV-G antibody, or any other palliativetherapy known to those skilled in the art.

Accordingly, in certain embodiments are provided methods of treating orpreventing a Respiratory Syncytial Virus (RSV) infection, ar at leastone symptom associated with RSV infection, comprising administering to apatient in need thereof or suspected of being in need thereof one ormore of the inventive antibodies or antigen-binding fragments thereofdisclosed herein and throughout, such as, e.g., one or more of theanti-RSV antibodies disclosed in Table 6, such that the RSV infection istreated or prevented, or the at least on symptom associated with RSVinfection is treated, alleviated, or reduced in severity.

In certain other embodiments are provided methods of treating orpreventing a Respiratory Syncytial Virus (RSV) infection, ar at leastone symptom associated with RSV infection, comprising administering to apatient in need thereof or suspected of being in need thereof a nucleicacid sequence encoding one or more of the inventive antibodies orantigen-binding fragments thereof, such nucleic acid sequenced disclosedin Table 6 and compliments thereof, such that the RSV infection istreated or prevented, or the at least on symptom associated with RSVinfection is treated, alleviated, or reduced in severity.

In additional embodiments are provided methods of treating or preventinga Respiratory Syncytial Virus (RSV) infection, ar at least one symptomassociated with RSV infection, comprising administering to a patient inneed thereof or suspected of being in need thereof a host cell harboringa nucleic acid sequence or an expression vector comprising such anucleic acid sequence, wherein such nucleic acid sequences is selectedfrom the group consisting of sequences disclosed in Table 6 andcompliments thereof, such that the RSV infection is treated orprevented, or the at least on symptom associated with RSV infection istreated, alleviated, or reduced in severity.

In additional embodiments are provided methods of treating or preventinga Respiratory Syncytial Virus (RSV) infection, ar at least one symptomassociated with RSV infection, comprising administering to a patient inneed thereof or suspected of being in need thereof a pharmaceuticalcomposition comprising either: one or more of the inventive antibodiesor antigen-binding fragments thereof as disclosed in Table 6; one ormore nucleic acid sequences or an expression vectors comprising such anucleic acid sequence, wherein such nucleic acid sequences are selectedfrom the group consisting of sequences disclosed in Table 6 andcompliments thereof; one or more host cells harboring one or morenucleic acid sequences or an expression vectors comprising such one ormore nucleic acid sequences, wherein such nucleic acid sequences areselected from the group consisting of sequences disclosed in Table 6 andcompliments thereof; and a pharmaceutically acceptable carrier and/orone or more excipients, such that the RSV infection is treated orprevented, or the at least on symptom associated with RSV infection istreated, alleviated, or reduced in severity.

In certain embodiments as provided methods of treating or preventingeither a Respiratory Syncytial Virus (RSV) infection or a humanmetapneumovirus (HMPV) infection, ar at least one symptom associatedwith said RSV infection or said HMPV infection, comprising administeringto a patient in need thereof or suspected of being in need thereof oneor more of the inventive antibodies or antigen-binding fragments thereofdisclosed herein and throughout, such as, e.g., one or more of theanti-RSV antibodies disclosed in Table 6, such that the RSV infection istreated or prevented, or the at least on symptom associated with RSVinfection is treated, alleviated, or reduced in severity. In certainembodiments, the one or more antibodies or antigen-binding fragmentsthereof comprises Antibody Number 340 as disclosed in Table 6.

In certain other embodiments are provided methods of treating orpreventing either a Respiratory Syncytial Virus (RSV) infection or ahuman metapneumovirus (HMPV) infection, ar at least one symptomassociated with said RSV infection or said HMPV infection, comprisingadministering to a patient in need thereof or suspected of being in needthereof a nucleic acid sequence encoding one or more of the inventiveantibodies or antigen-binding fragments thereof, such nucleic acidsequenced disclosed in Table 6 and compliments thereof, such that theRSV infection is treated or prevented, or the at least on symptomassociated with RSV infection is treated, alleviated, or reduced inseverity. In certain embodiments, the one or more antibodies orantigen-binding fragments thereof comprises Antibody Number 340 asdisclosed in Table 6.

In additional embodiments are provided methods of treating or preventingeither a Respiratory Syncytial Virus (RSV) infection or a humanmetapneumovirus (HMPV) infection, ar at least one symptom associatedwith said RSV infection or said HMPV infection, comprising administeringto a patient in need thereof or suspected of being in need thereof ahost cell harboring a nucleic acid sequence or an expression vectorcomprising such a nucleic acid sequence, wherein such nucleic acidsequences is selected from the group consisting of sequences disclosedin Table 6 and compliments thereof, such that the RSV infection istreated or prevented, or the at least on symptom associated with RSVinfection is treated, alleviated, or reduced in severity. In certainembodiments, the one or more antibodies or antigen-binding fragmentsthereof comprises Antibody Number 340 as disclosed in Table 6.

In additional embodiments are provided methods of treating or preventingeither a Respiratory Syncytial Virus (RSV) infection or a humanmetapneumovirus (HMPV) infection, ar at least one symptom associatedwith said RSV infection or said HMPV infection, comprising administeringto a patient in need thereof or suspected of being in need thereof apharmaceutical composition comprising either: one or more of theinventive antibodies or antigen-binding fragments thereof as disclosedin Table 6; one or more nucleic acid sequences or an expression vectorscomprising such a nucleic acid sequence, wherein such nucleic acidsequences are selected from the group consisting of sequences disclosedin Table 6 and compliments thereof; one or more host cells harboring oneor more nucleic acid sequences or an expression vectors comprising suchone or more nucleic acid sequences, wherein such nucleic acid sequencesare selected from the group consisting of sequences disclosed in Table 6and compliments thereof; and a pharmaceutically acceptable carrierand/or one or more excipients, such that the RSV infection is treated orprevented, or the at least on symptom associated with RSV infection istreated, alleviated, or reduced in severity. In certain embodiments, theone or more antibodies or antigen-binding fragments thereof comprisesAntibody Number 340 as disclosed in Table 6.

Combination Therapies

As noted above, according to certain embodiments, the disclosed methodscomprise administering to the subject one or more additional therapeuticagents in combination with an antibody to RSV-F and or HMPV. As usedherein, the expression “in combination with” means that the additionaltherapeutic agents are administered before, after, or concurrent withthe pharmaceutical composition comprising the anti-RSV-F antibody. Theterm “in combination with” also includes sequential or concomitantadministration of the anti-RSV-F antibody and a second therapeuticagent.

For example, when administered “before” the pharmaceutical compositioncomprising the anti-RSV-F antibody, the additional therapeutic agent maybe administered about 72 hours, about 60 hours, about 48 hours, about 36hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours,about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30minutes, about 15 minutes or about 10 minutes prior to theadministration of the pharmaceutical composition comprising theanti-RSV-F antibody. When administered “after” the pharmaceuticalcomposition comprising the anti-RSV-F antibody, the additionaltherapeutic agent may be administered about 10 minutes, about 15minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours,about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24hours, about 36 hours, about 48 hours, about 60 hours or about 72 hoursafter the administration of the pharmaceutical composition comprisingthe anti-RSV-F antibodies. Administration “concurrent” or with thepharmaceutical composition comprising the anti-RSV-F antibody means thatthe additional therapeutic agent is administered to the subject in aseparate dosage form within less than 5 minutes (before, after, or atthe same time) of administration of the pharmaceutical compositioncomprising the anti-RSV-F antibody, or administered to the subject as asingle combined dosage formulation comprising both the additionaltherapeutic agent and the anti-RSV-F antibody.

Combination therapies may include an anti-RSV-F antibody of theinvention and any additional therapeutic agent that may beadvantageously combined with an antibody of the invention, or with abiologically active fragment of an antibody of the invention.

For example, a second or third therapeutic agent may be employed to aidin reducing the viral load in the lungs, such as an antiviral, forexample, ribavirin. The antibodies may also be used in conjunction withother therapies, as noted above, including a toxoid, a vaccine specificfor RSV, a second antibody specific for RSV-F, or an antibody specificfor another RSV antigen, such as RSV-G.

Diagnostic Uses of the Antibodies

The inventive anti-RSV antibodies and antigen-binding fragments thereofmay also be used to detect and/or measure RSV and/or HMPV in a sample,e.g., for diagnostic purposes. It is envisioned that confirmation of aninfection thought to be caused by RSV and/or HMPV may be made bymeasuring the presence of the virus through use of any one or more ofthe antibodies of the invention. Exemplary diagnostic assays for RSVand/or HMPV may comprise, e.g., contacting a sample, obtained from apatient, with an anti-RSV-F and/or HMPV antibody of the invention,wherein the anti-RSV-F and/or HMPV antibody is labeled with a detectablelabel or reporter molecule or used as a capture ligand to selectivelyisolate the virus containing the F protein from patient samples.Alternatively, an unlabeled anti-RSV-F and/or HMPV antibody can be usedin diagnostic applications in combination with a secondary antibodywhich is itself detectably labeled. The detectable label or reportermolecule can be a radioisotope, such as ³H, ¹⁴C, ³²P, ³⁵S, or ¹²⁵I; afluorescent or chemiluminescent moiety such as fluoresceinisothiocyanate, or rhodamine; or an enzyme such as alkaline phosphatase,β-galactosidase, horseradish peroxidase, or luciferase. Specificexemplary assays that can be used to detect or measure RSV containingthe F protein and/or HMPV in a sample include enzyme-linkedimmunosorbent assay (ELISA), radioimmunoassay (RIA), andfluorescence-activated cell sorting (FACS).

Samples that can be used in RSV and/or HMPV diagnostic assays accordingto the present invention include any tissue or fluid sample obtainablefrom a patient, which contains detectable quantities of RSV-F proteinand/or HMPV, or fragments thereof, under normal or pathologicalconditions. Generally, levels of RSV-F and/or HMPV in a particularsample obtained from a healthy patient (e.g., a patient not afflictedwith a disease or condition associated with the presence of RSV-F and/orHMPV) will be measured to initially establish a baseline, or standard,level of the F protein from RSV and/or HMPV. This baseline level ofRSV-F and/or HMPV can then be compared against the levels of RSV-Fand/or HMPV measured in samples obtained from individuals suspected ofhaving an RSV and/or HMPV infection, or symptoms associated with suchinfection.

EXAMPLES

Applicants have comprehensively profiled the human antibody response toRSV fusion protein (F) by isolating and characterizing 133 RSVF-specific monoclonal antibodies from the memory B cells of a healthyadult donor, and used these antibodies to comprehensively map theantigenic topology of RSV F. The antibody response to RSV F wasdetermined to be comprised of a broad diversity of clones that targetseveral antigenic sites. Nearly half of the most potent antibodiestarget a previously undefined site of vulnerability near the apex of theprefusion conformation of RSV F (preF), providing strong support for thedevelopment of RSV antibodies that target this region, as well asvaccine candidates that preserve the membrane-distal hemisphere of thepreF protein. Additionally, this class of antibodies displayedconvergent sequence features, thus providing a future means to rapidlydetect these types of antibodies in human samples. Many of theantibodies that bound preF-specific surfaces from this donor were over100 times more potent than palivizumab, and one antibodycross-neutralized human metapneumovirus (HMPV). Taken together, theresults have implications for the design and evaluation of RSV vaccineand antibody-based therapeutic candidates, and offer new options forpassive prophylaxis.

Large-Scale Isolation of RSV F-Specific Monoclonal Antibodies fromHealthy Adult Human Donors

In order to comprehensively profile the human antibody response to RSVF, Applicants isolated and characterized 133 monoclonal antibodies fromthe memory B cells of a healthy adult donor (“donor 006”). Although thisdonors did not have a documented history of RSV infection, healthyadults are expected to have had multiple RSV infections throughout life(26).

The magnitude of the memory B cell response in this donor to RSV F wasassessed by staining peripheral B cells with a mixture of fluorescentlylabeled pre- and postfusion RSV F sorting probes (FIG. 6A through 6B)(11, 15). Both proteins were dual-labeled in order to eliminatebackground due to non-specific fluorochrome binding (27). Flowcytometric analysis revealed that 0.04-0.18% of class-switched (IgG⁺ andIgA⁺) peripheral B cells were specific for RSV F (FIG. 1A and Figure B),which is significantly lower than the percentage of RSV F-specific cellsobserved after experimental RSV infection and suggests that this donorwas probably not recently exposed to RSV (28). Notably, index sortingshowed that 17-38% of circulating RSV F-specific B cells express IgA,indicating that IgA memory B cells to RSV F are present in peripheralblood (FIG. 1B).

Approximately 200 RSV F-specific B cells were single-cell sorted fromthe donor sample, and antibody variable heavy (VH) and variable light(VL) chain genes were rescued by single-cell PCR (29). One hundredthirty-three (133) cognate heavy and light chain pairs were subsequentlycloned and expressed as full-length IgGs in an engineered strain ofSaccharomyces cerevisiae for further characterization (30). Preliminarybinding studies showed that approximately 80% of antibodies cloned fromRSV F glycoprotein (F)-specific B cells bound to recombinant RSV Fproteins.

Sequence Analysis of RSV F-Specific Antibody Repertoires

Sequence analysis of the isolated monoclonal antibodies revealed thatthe RSV-F specific repertoire was highly diverse, containing over 70unique lineages (FIG. 1C and Table 2). This result is in stark contrastto the relatively restricted repertoires observed in HIV-infectedpatients (31), or in healthy donors after influenza vaccination (32).Compared to non-RSV-reactive antibodies (33), the RSV F-specificrepertoires were skewed, generally, toward certain VH germline genes(VH1-18, VH1-2, VH1-69, VH2-70, VH4-304, and VH5-51) (FIG. 1D and Table2) and longer heavy chain third complementarity-determining region(CDRH3) lengths (generally, approximately 14-18 amino acids in length;FIG. 1E and Table 2). Interestingly, a bias toward VH1-69 has also beenobserved in anti-HIV-1, anti-influenza, and anti-HCV repertoires(34-36), and recent studies have shown that there is a significantincrease in the relative usage of VH1-18, VH1-2, and VH1-69 during acutedengue infection (37). Hence, it appears that these particular germlinegene segments may have inherent properties that facilitate recognitionof viral envelope proteins.

The average level of somatic hypermutation (SHM) ranged generallybetween 16 and 30 nucleotide substitutions per VH gene (excluding CDRH3)(FIG. 1F and Table 2), which is comparable to the average level of SHMobserved in anti-influenza antibody repertoires (32, 38) and consistentwith the recurrent nature of RSV infection (26). Interestingly, severalantibodies contained 40 or greater VH gene nucleotide substitutions,suggesting that multiple rounds of RSV infection can result inantibodies with very high levels of somatic hypermutation (SHM).

A Large Proportion of Antibodies Bind Exclusively to preF

We next measured the apparent binding affinities of the IgGs tofurin-cleaved RSV F ectodomains stabilized in the prefusion (DS-Cav1) orpostfusion (F ΔFP) conformation using biolayer interferometry (11, 15).A relatively large proportion of the antibodies (36-67%) boundexclusively to preF (FIG. 2A and Figure B; Table 3). The vast majorityof remaining antibodies bound to both pre- and postF, with only 5-7% ofantibodies showing exclusive postF specificity (FIG. 2A and Figure B;Table 3). The low prevalence of postF-specific antibodies in these donorrepertoires is consistent with the observation that less than 10% ofanti-RSV F serum-binding activity specifically targets postF (8).Interestingly, however, the majority of cross-reactive antibodies boundwith higher apparent affinity to postF (FIG. 2A; Table 3), suggestingthat these antibodies were probably elicited by and/or affinity maturedagainst postF in vivo. Hence, the significantly higher proportion ofpreF- versus postF-specific antibodies is likely due to the higherimmunogenicity of the unique surfaces on preF compared to postF, ratherthan an increased abundance of preF in vivo. Finally, as expected basedon the relatively high degree of sequence conservation between RSVsubtypes, most of the antibodies showed binding reactivity to F proteinsderived from both subtypes A and B (FIG. 2C; Table 3).

Since certain antiviral antibody specificities have been associated withpoly- and autoreactivity (39-41), we also tested the RSV antibodies forpolyreactivity using a previously described high-throughput assay thatcorrelates with down-stream behaviors such as serum clearance (42, 43).One hundred and seventy-seven clinical antibodies, as well as severalbroadly neutralizing HIV antibodies, were also included for comparison.Interestingly, in contrast to many previously described HIV broadlyneutralizing antibodies, the vast majority of RSV F-specific antibodieslacked significant polyreactivity in this assay (FIG. 2D).

RSV F-Specific Antibodies Target Six Major Antigenic Sites

To map the antigenic specificities of the RSV F-specific antibodies,Applicants first performed competitive binding experiments using apreviously described yeast-based assay (44). Antibodies were initiallytested for competition with D25, AM14 and MPE8-three previouslydescribed preF-specific antibodies (10, 17, 21)—and motavizumab, anaffinity-matured variant of palivizumab that binds to both pre- andpostF (10, 11, 45). Non-competing antibodies were then tested forcompetition with a site IV-directed mAb (101F) (46), a site I-directedantibody (Site I Ab), and two high affinity antibodies (High Affinity AbI and High Affinity Ab 2, respectively) that did not strongly competewith each other or any of the control antibodies. Each antibody wasassigned a bin based on the results of this competition assay (see,e.g., Table 4).

In order to confirm and increase the resolution of our epitopeassignments, the binding of each antibody to a panel of preF variantswas measured using a luminex-based assay. Each variant contained 2-4mutations clustered together to form a patch on the surface of preF. Atotal of nine patches that uniformly covered the surface of preF weregenerated (FIG. 7A through FIG. 7C). Deglycosylated preF was alsoincluded to identify antibodies targeting glycan-dependent epitopes.Binding of each antibody to the 10 preF variants was compared to that ofwild-type preF and used to assign a patch (see, e.g., Table 4).Previously characterized antibodies D25, AM14 and motavizumab were usedto validate the assay (se, e.g., FIG. 7C and Table 4). The combined binand patch data were then used to assign each antibody to a singleantigenic site (FIG. 3A through FIG. 3G), which were defined based onpreviously determined structures, resistance mutations, and secondarystructure elements of the F protein. Overall, these data show that thelarge majority of isolated antibodies target six dominant antigenicsites on prefusion RSV F (0, I, II, III, IV, and V). Interestingly, onlya small proportion of the isolated antibodies had binding profilessimilar to that of AM14, suggesting that antibodies targeting thisquaternary epitope are not commonly elicited during natural infection.None of the antibodies were sensitive to deglycosylation of F,demonstrating that glycan-dependent antibodies are also rarely elicitedby natural RSV infection.

Analysis of the preF- and postF-binding activities of the antibodiestargeting each antigenic site (see, e.g., FIG. 3C through FIG. 3G; Table4) revealed that three sites are primarily found on preF (0, III, andV). Antibodies targeting site Ø and site III have been previouslydescribed (10, 17), and these sites are located on the top and side ofthe preF spike, respectively. Approximately 18% of the antibodies fromthis donor recognized site Ø and approximately 20% recognized site III.A relatively large proportion of antibodies from this donor(approximately 26%) recognized the third preF-specific site, which hasnot been previously described and therefore has been designated hereinas region site V (See, e.g., FIG. 3C through FIG. 3G; Table 4). Themajority of site V antibodies competed with D25, MPE8 and motavizumab,which was unexpected given the distance between the epitopes recognizedby these three antibodies. The patch mutant analysis revealed that theseantibodies interact with the α3 helix and β3/β4 hairpin of preF. Thisregion is located between the epitopes recognized by D25, MPE8, andmotavizumab, explaining the unusual competition profile observed forthis class of antibodies (See, e.g., FIG. 8 ). In addition to the threeprimarily preF-specific sites, a large number of the antibodies thatrecognized antigenic site IV were preF-specific, likely due to contactswith β22, which dramatically rearranges during the transition from pre-to postF. In summary, the epitope mapping data show that the largemajority of isolated antibodies target six dominant antigenic sites,approximately half of which are exclusively expressed on preF.

Highly Potent Neutralizing Antibodies Target preF-Specific Epitopes

The antibodies were next tested for neutralizing activity against RSVsubtypes A and B using a previously described high-throughputneutralization assay (15). Greater than 70% of the isolated antibodiesshowed neutralizing activity, and approximately 35%-40% neutralized withhigh potency (IC₅₀≤0.05 μg/ml) (see, e.g., FIG. 4A and FIG. 4B; Table3). Notably, several clonally unrelated antibodies were ≥5.0-fold morepotent than D25 and ≥100-fold more potent than palivizumab (see, e.g.,FIG. 4A; Table 3). Interestingly, there was no correlation betweenneutralization potency and level of SHM, suggesting that extensive SHMis not required for potent neutralization of RSV. Consistent with thebinding cross-reactivity data, the majority of neutralizing antibodiesshowed activity against both subtype A and B (FIG. 4A through FIG. 4C;Table 3).

The relationship between preF- and postF-binding affinity andneutralization potency was next investigated, which clearly demonstratedthat the majority of highly potent antibodies bound preferentially orexclusively to preF (see, e.g., FIG. 4D through FIG. 4G; Table 3).Quantifying this difference revealed that more than 80% of highly potentantibodies (IC₅₀<0.05 μg/ml) were specific for preF (See, e.g., FIG. 9 ;Table 3) and that the median IC₅₀ for preF-specific antibodies was morethan 8-fold lower than for pre- and postF cross-reactive antibodies and80-fold lower than antibodies that specifically recognized postF (see,e.g., FIG. 4E; Table 3). Importantly, there was a positive correlationbetween preF binding and neutralization (P<0.001, r=0.24), and theapparent preF KDs generally corresponded well with the neutralizationIC₅₀s (see, e.g., FIG. 5A; Table 3). In contrast, there was nocorrelation between neutralization potency and postF affinity (P=0.44,r=−0.07) (see, e.g., FIG. 5B; Table 3). This result is compatible withthe occupancy model of antibody-mediated neutralization (47), andsuggests that DS-Cav1 is a faithful antigenic mimic of the native preFtrimer. Notably, very few antibodies neutralized with IC₅₀s lower than100 pM, which is consistent with the previously proposed ceiling toaffinity maturation (48, 49).

The relationship between neutralization potency and antigenic site wasnext analyzed. The results, provided in, e.g., FIG. 5C, Table 3, andTable 4, collectively, indicated that over 60% of the highly potentneutralizing antibodies targeted antigenic sites Ø and V, which are twoof the three prefusion-F specific sites. In contrast, antibodiestargeting sites III and IV showed a wide range of neutralizationpotencies, and antibodies targeting sites I and II were generallymoderate to non-neutralizing. Similar results were obtained usingbinding affinities and neutralization potencies measured for subtype B(See, e.g., FIG. 10A through FIG. 10C; Table 3 and Table 4).Interestingly, a subset of site IV-directed antibodies neutralized withsubstantially lower potency than would be expected based on preF bindingaffinity (see, e.g., FIG. 5A; Table 3). This result may suggest thatcertain epitopes within site IV are less exposed in the context of thenative envelope spike expressed on the crowded surface of the virionthan on recombinant preF.

Several Antibodies Cross-Neutralize RSV and HMPV

Given that the RSV and human metapneumovirus (HMPV) F proteins share 33%amino acid identity, and certain RSV F-specific antibodiescross-neutralize HMPV (17, 50), the antibodies from this donor weretested for neutralizing activity against HMPV. Of the 133 antibodiestested, one neutralized HMPV (see, e.g., Table 5). Sequence analysisrevealed that this antibody represents the VH1-46 germline gene andcontains a significant degree of somatic hypermutation (See, e.g., Table2 and sequence listing). This cross-neutralizing antibody bound to boththe preF and PostF and competed with MPE8 (See, e.g., Table 5), inagreement with previous studies indicating that MPE8 cross-neutralizesfour pneumoviruses, including RSV and HMPV (17). This result suggests,inter alia, that highly conserved epitopes are relatively immunogenic inthe context of natural RSV and/or HMPV infection.

Affinity Maturation of RSV F-Specific Antibodies:

Some embodiments refer to affinity matured antibodies of any of theantibodies listed in Table 6 (each understood as a “parent” antibody”for producing an affinity matured variant). Affinity matured antibodiesmay be produced by mutagenesis of any one or more of the CDRs of theparent antibody. According to a specific embodiment, the inventionprovides for affinity matured variants comprising one or more pointmutations e.g., 0, 1, 2, or 3 point mutations in each of the CDRsequences, of any of the antibodies listed in Table 6, or of an antibodycomprising the six CDR sequences of any of the antibodies listed inTable 6. Affinity matured variants can be produced by any affinitymaturation method employing standard mutagenesis techniques, e.g., foroptimizing the binding characteristics, such as increasing affinity ofbinding, or increasing Kon, or decreasing Koff, and can be characterizedby a K_(D) difference of at least 2 fold, 5 fold, 1 log, or 2 logs, or 3logs, as compared to the parent antibody. Such affinity maturedantibodies still have the same binding specificity as the parentantibody and e.g., an optimized affinity of binding the target epitope.

Selected anti RSV antibodies were identified for affinity maturation.Oligos were ordered which comprised CDRH1, CDRH2, CDRH3, CDRL1, CDRL2,and CDRL3 sequences that were variegated via NNK diversity. The NNKoligos were incorporated into the parent HC or LC via DNA shuffling, asdescribed previously (Stemmer W P et al., DNA shuffling by randomfragmentation and reassembly: In vitro recombination for molecularevolution. Proc Natl Acad Sci USA. 1994 Oct. 25; 91(22):10747-51). Thelibrary was then created by transforming the VH and VL PCR products intoyeast already containing either the light chain or heavy chain plasmidof the parent. The diversified libraries were then selected using flowcytometry. For each FACS round, the libraries were affinity pressuredusing decreasing amounts of antigen and clones with improved bindingaffinities were sorted and propagated. Once improved binding populationswere observed by flow cytometry (typically two rounds of selection),single yeast clones were be picked for sequencing and characterization(Table 6).

A specific embodiment refers to affinity matured variants of theantibody 267 in Table 6. Notably, each of the antibodies numbered365-372 is an affinity matured variant of the antibody numbered 267 inTable 6.

Antibody Production and Purification of Affinity Matured Antibodies

Yeast clones were grown to saturation and then induced for 48 h at 30°C. with shaking. After induction, yeast cells were pelleted and thesupernatants were harvested for purification. IgGs were purified using aProtein A column and eluted with acetic acid, pH 2.0. Fab fragments weregenerated by papain digestion and purified over KappaSelect (GEHealthcare LifeSciences).

RSV In Vitro Neutralization in ELISA Based Microneutralization Assays

In vitro RSV neutralization was tested in ELISA basedMicroneutralization Assays using RSV-A strain A2 (ATCC, VR1540P). Virus(at a final multiplicity of infection of approximately 0.25) was addedto 96-well plates containing serially diluted mAbs in serum-free MEM andpre-incubated for 30 min at 4° C. Freshly trypsinized Hep-2 cells(1.5×10E⁴ cells/well) were then added to each well in MEM supplementedwith 5% FCS. Following incubation for 4 days at 37° C. and 5% CO₂,medium was aspirated and cells were washed twice with 200 μl PBS/well,air-dried and fixed with 100 μl Acetone (80%). RSV replication wasmeasured by quantification of expressed viral proteins by ELISA. Forthis purpose, fixed cells were washed 2×times with PBS-0.1% Tween-20,blocked with 1% skimmed milk in PBS for 1 hour at RT and then stainedwith a polyclonal goat-anti RSV antibody preparation (BioRad,#7950-0004) for 1 hour at RT in blocking buffer. A donkey anti-goat IgGHRP conjugate was used as detection reagent and 1 step-Ultra TMB (ThermoFisher Scientific, #34209) as substrate. % inhibition of virusreplication was calculated relative to control cells infected with virusin absence of neutralizing antibodies. An isotype matched control mAbwas included in all experiments. mAb potency is expressed ashalf-maximal inhibitory concentration that resulted in 50% reduction invirus replication (IC₅₀). Results are provided in FIG. 11 anddemonstrate that all mAbs were able to neutralize RSV-A2 in thissetting, with a broad range of IC₅₀ values.

DISCUSSION

An in-depth understanding of the human antibody response to RSVinfection will aid the development and evaluation of RSV vaccine andtherapeutic and/or prophylactic antibody candidates for the treatmentand/or prevention of RSV infection. Although previous studies havecoarsely mapped the epitopes targeted by RSV-specific neutralizingantibodies in human sera (4, 8), the specificities and functionalproperties of antibodies induced by natural RSV infection have remainedlargely undefined. As disclosed herein, preF- and postF-stabilizedproteins (11, 15), a high-throughput antibody isolation platform, and astructure-guided collection of prefusion F mutants, were used toclonally dissect the human memory B cell response to RSV F in anaturally infected adult donor, and highly potent and selectiveRSV-neutralizing—as well as highly potent anti-RSV/anti-HMPVcross-selective and cross-neutralizing—were isolated and characterized.

In the repertoire analyzed, the ratio of preF-specific antibodies tothose that recognize both pre- and postF was slightly greater than 1:1(See, e.g., FIG. 2B). These values are somewhat lower than thosereported for human sera, which showed approximately 70% of anti-F serumbinding is specific for preF (8). This discrepancy may be the result ofdifferences between the levels of individual antibodies in serum,differences in the B cell phenotypes achieved for a particularspecificity, or variation between donors. Despite these minordifferences, the results of both studies suggest that preF-specificepitopes and epitopes shared by pre- and postF are immunogenic duringnatural RSV infection, whereas the unique surfaces on postF aresignificantly less immunogenic.

The repertoire analysis disclosed herein revealed that the largemajority of RSV F-specific antibodies target six dominant antigenicsites on prefusion RSV F: Ø, I, II, III, IV, and V. These sites weredefined based on previously determined structures, epitopebinning/competition assays, resistance mutations, and secondarystructure elements of the preF protein. It is important to note that thenomenclature for describing RSV F antigenic sites has evolved over time(6, 51-57), and previous mapping efforts were based on the postfusionconformation of F and did not include surfaces present exclusively onpreF. The crystal structure of preF has provided critical informationabout F structure and function as well as new reagents to map antibodybinding sites on the unique surfaces of preF and surfaces shared withpostF. To a first approximation, each antibody can be assigned primarilyto one of these sites. However, it is likely that antibody epitopescover the entire surface of F and that there are antibodies that bindtwo or more adjacent antigenic sites within a protomer and quaternaryantibodies that bind across protomers.

Importantly, the results disclosed herein show that the most potentlyneutralizing antibodies target antigenic sites Ø and V, both of whichare located near the apex of the preF trimer. These findings areconsistent with results obtained from human sera mapping, whichdetermined that the majority of neutralizing activity can be removed bypre-incubation with preF (4, 8) and that preF-specific sites other thansite Ø make up a considerable fraction of preF-specific neutralizingantibodies (8). Although antigenic site Ø has been shown to be a targetof potently neutralizing antibodies (8, 10), the interaction ofantibodies with site V is less well understood. Interestingly, it wasfound that the majority of site V-directed antibodies share severalconvergent sequence features, suggesting that it may be possible torapidly detect these types of antibodies in human samples usinghigh-throughput sequencing technology (58). Applicants anticipate thisfinding to be particularly advantageous in profiling antibody responsesto RSV vaccine candidates that aim to preserve the apex of the preFtrimer.

The extensive panel of antibodies described here provides newopportunities for passive prophylaxis, as well as for treatment of RSVinfection. A large number of these antibodies neutralize RSV morepotently than D25, which serves as the basis for MEDI8897—a monoclonalantibody that is currently in clinical trials for the prevention of RSVin young, at risk children (59). Additionally, a subset of theseantibodies were demonstrated to cross-neutralize HMPV.

The development of an effective RSV vaccine has presented a number ofunique challenges, and selection of the optimal vaccination strategywill be of the utmost importance. The in-depth analysis of the humanantibody response to natural RSV infection presented here providesinsights for the development of such a vaccine. Importantly, the resultssuggest that immunization of pre-immune donors with preF immunogenswould be expected to boost neutralizing responses, whereas the use ofpostF immunogens would likely expand B cell clones with moderate or weakneutralizing activity. Similarly, immunization of RSV naïve infants withpreF immunogens would be expected to activate naïve B cells targetingepitopes associated with substantially more potent neutralizing activitycompared to postF immunogens. In addition, the ideal RSV vaccine shouldpreserve antigenic sites Ø and V, since these sites are targeted by themost highly potent antibodies elicited in response to natural RSVinfection.

Accordingly, disclosed herein are highly selective and potent anti-RSVantibodies, as well as highly potent cross-neutralizing anti-RSV andanti-HMPV antibodies, as well as vaccine candidates, for the treatmentand or prophylaxis of RSV and/or HMPV infection. Additionally, thereagents disclosed here provide a useful set of tools for the evaluationof clinical trials, which will be critical for selecting the optimal RSVvaccination or antibody-based therapeutic strategy from the manycurrently under investigation (60).

TABLE 1 Antigenic sites targeted by prototypic RSV antibodies Antigenicsite Prototypic antibodies Ø D25, 5C4, AM22 (10, 16) I 131-2a, 2F II1129, palivizumab, motavisumab (6) III MPE8 (17) IV 101F (57), mAb 19(19)

TABLE 2 Germline usage and sequence information of anti-RSV antibodiesVH LC Number of Number of Antibody germline germline nucleotidenucleotide number gene gene CDR H3 CDR L3 Lineage substitutionssubstitutions Name (Ab #) usage usage Sequence Sequence number in VH inVL ADI- 232 VH4- VK1- AGTNY QQSYSTPL 4 10 8 18875 34 39 GEVNT T SNQYFFGMDV ADI- 233 VH4- VK3- ARDVG QQYGSSP 44 12 4 18876 304 20 TLVLPT LVTVAYYY GMDV ADI- 234 VH1- VK2- ARESG MQAIHWP 52 9 8 18877 18 30 ATAAA RTMFDY ADI- 235 VH4- VK3- ARDGG QQYGASP 23 12 6 18878 304 20 YDHVW WTGTHRY FDK ADI- 236 VH1- VK2- ARD VP MQGTHW 46 9 12 18879 18 30 GHGAA PPAFMDV ADI- 237 VH1- VK2- ARDPP MQGTHW 36 8 7 18880 18 30 AYAAT PPT LMDVADI- 238 VH1- VK3- ARDAY QQYGSSF 21 19 9 18882 69 20 EVWTG LT SYLPPF DYADI- 239 VH1- VK1- ARVPES QQGTSFPF 79 30 6 18883 69 12 LVASN T AYAV ADI-240 VH1-3 VK2- ARGQIV MQTLQTPI 57 8 1 18884 28 VIPRAN T FWFDP ADI- 241VH4- VK3- ARDGG QQYGTSP 22 13 8 18885 304 20 YDHIW WT GTHRY FAL ADI- 242VH1- VK1-9 ARVFF QQLHSDF 76 20 8 18887 69 GTCGG QT ASCFPS DL ADI- 243VH3- VK3- ARDHA QQYGSFP 24 8 10 18888 33 20 STPYY WT MDV ADI- 244 VH4-VK1- AGTNV QQSYSVP 3 25 12 18889 34 39 GFVNT LT HYYFG MDV ADI- 245 VH1-VK3- ARDAY QQYGSSF 21 27 10 18890 69 20 EVWTG LT SYLPPF DY ADI- 246 VH1-VK3- ARDAY QQYGSSF 21 22 10 18891 69 20 EVWTG LT SYLPPF DY ADI- 247 VH1-VK2- ARDSFS MQATQW 39 7 1 18892 18 30 LTGAG PRT FPDY ADI- 248 VH3- VL1-ARLGY QSYDLSLS 61 8 3 18893 21 40 GGNPE SSRV LDY ADI- 249 VH3- VL1-ARGAS QSYDSLS 54 11 5 18894 30 40 YYYVS ASWV SDLGY ADI- 250 VH5- VK1-ASVML QPYDNLP 84 12 1 18895 51 33 RGIM PPLT ADI- 251 VH3- VK3- ARAPYQQYSIWP 16 10 6 18896 30 15 DIWSG QT YCLDY ADI- 252 VH3-7 VK4-1 ARDTPQQYYSSP 42 11 8 18897 DVLRH QT LEWPP VGAFDI ADI- 253 VH1- VK2- ARESGMQAIHWP 52 9 8 18898 18 30 ATAAA RT MFDY ADI- 254 VH3- VK3- ARAPYQQYSIWP 16 10 6 18899 30 15 DIWSG QT YCLDY ADI- 255 VH3- VK1-5 ARDQEQQYYTYY 38 22 7 18900 23 VELIDD S AFDF ADI- 256 VH1-2 VL1- ARSSLVGTWDASL 72 18 8 18901 51 GASPNF SAAMV DF ADI- 257 VH4- VL3- ARSTWQVWDSSP 73 8 7 18902 59 21 DYGDH DHPYV FPFDY ADI- 258 VH1- VK2- ARD VPMQGTHW 46 9 12 18903 18 30 GHGAA PPA FMDV ADI- 259 VH1- VK2- ARDPPMQGTHW 36 8 7 18904 18 30 AYAAT PPT LMDV ADI- 260 VH4- VK1-5 ACKRAQQYHVYF 1 29 2 18905 39 DADDV PLT DYVAG LTGFP WYFDV ADI- 261 VH3- VK3-ARDHA QQYGSFP 24 8 10 18906 33 20 STPYY WT MDV ADI- 262 VH1- VK3- ARGCCQQRTTGV 55 21 7 18907 69 11 GAVAG T FQH ADI- 263 VH3- VL1- VRGVL QSYDYSL98 16 7 18908 21 40 PGGTG NWV GGWFD s ADI- 264 VH4- VK3- ARDLG QVYSSSPP27 13 9 18909 304 20 KPLWD IT GHYYY GVDV ADI- 265 VH1- VK2- ARTAAMQTLQTP 74 8 3 18910 69 28 LGPPGT WT IVGYM DV ADI- 266 VH5- VK1- ARLGIGLQFDNLPP 60 12 7 18911 51 33 AAARN T Y ADI- 267 VH3- VL1- ARDLLP QSYDSRL31 6 3 18912 21 40 VERGP GGSV AFDI ADI- 268 VH5- VK1- ARQIGG QQSDTTPF 6713 6 18913 51 39 LVCSSE T SCYFY GMDV ADI- 269 VH3- VL1- ATDSR QSYDDSL 864 3 18915 15 40 RLYDS TGWV RGFYSS AFDV ADI- 270 VH5- VK1- ARQIGGQQSDTTPF 67 13 6 18916 51 39 LVCSSE T SCYFY GMDV ADI- 271 VH3- VL1-VRGVL QSYDYSL 98 16 7 18917 21 40 PGDTG NWV GGWFD S ADI- 272 VH5- VK3-ARLPV QQYNNW 62 8 13 18918 51 15 GSYYY LSWT FNL ADI- 273 VH4- VK2- ARTSYMQGLQIP 75 22 4 18919 31 28 AGRML WT DR ADI- 274 VH3- VL1- AKVRN GTWDTSL12 10 14 18920 30 51 EAWEL RAGV LGDAL DV ADI- 275 VH1- VK1- ATPTPVQQSYIIPY 88 15 2 18921 24 39 GATDY T ADI- 276 VH4-b VK3- ASRRGS QQYNNWP83 22 8 18922 15 GWFFD PGGT S ADI- 277 VH3- VL1- ARDWP QSYDSSLS 48 0 018923 21 40 NSSSSP GFYV NWFDP ADI- 278 VH5- VL1- ARCSLS QSYDSSLS 18 9 1118924 51 40 CDYYG GFYV VNL ADI- 279 VH3- VK3- AKPIVG QQRSNWY 9 8 0 1892530 11 PTTGYF T DY ADI- 280 VH1- VK2- ARDPP MQGTHGR 36 19 8 18926 18 30ASAAA GIS MLDY ADI- 281 VH1-2 VK1- ASQSSP QQSFTPQF 82 21 21 18927 13YTPGA T LDV ADI- 282 VH1- VL7- ARDIE LLSYSGA 25 15 8 18928 69 46 WFVLMRPV DPITSY YPMDV ADI- 283 VH3- VL1- ARDAVI AAWDDSL 19 9 6 18929 11 44WGPV NGPV AVHYQ YYADV ADI- 284 VH1- VK3- ARDAY QQYGSSF 21 14 8 18930 6920 EVWTG LT SYLPPF DY ADI- 285 VH3- VK3- TRDDIL QQYDNWP 92 6 6 18931 4915 TGFYD PYT RSYYY GIHV ADI- 286 VH4- VK3- ARDLG QQRSTWP 29 25 10 18932304 11 TLAFDP T YYYYG IDV ADI- 287 VH1- VKl- ARRGY QQSYIRPI 69 26 1018933 46 39 PDSGSY T PLDY ADI- 288 VH4- VK3- ARDLG QQRSNGV 30 19 6 18935304 11 YSSSSP LT AFYYGI DF ADI- 289 VH1-8 VK1- ASQSSP QLNSGAL 82 26 1218936 39 YTPGA FT MGV ADI- 290 VH4- VK3- ARDVG QQYGGSP 45 25 10 18937304 20 VYSGY PVT DVFHY YGMDV ADI- 291 VH3- VK1-5 ARDLW QQYNSWA 32 15 1018938 74 TTSPYF DL ADI- 292 VH4- VK1- AGTNY QQSYSAP 4 3 7 18939 34 39GEVNT LT SNQYFF GMDV ADI- 293 VH1-8 VK1- ASQSSP QLNSGAL 82 33 14 1894039 YTPGA FT MDV ADI- 294 VH5- VK3- GQAVA QHYNNWP 90 7 5 18941 51 15GGEYF RG HH ADI- 295 VH4- VK3- ARDLG QQRSNWP 28 19 6 18942 304 11 TANNYPYT YFGMD V ADI- 296 VH4-b VK3- AGAFW QQYSSSPL 2 38 7 18943 20 EVWTG TLYSPPF DF ADI- 297 VH1- VK2- ARDPA MQGTHW 34 20 8 18944 18 30 VDAIP PLTMLDY ADI- 298 VH3- VL2- AKEEW SSYSTNSA 7 8 3 18946 30 14 LVPAY P ADI-299 VH3- VK3- ARAPY QQYSIWP 16 16 7 18947 30 15 DIWSG QT YCLDY ADI- 300VH3- VK3- ARAPY QQYSIWP 16 13 7 18948 30 15 DIWSG QT YCLDY ADI- 301 VH1-VK2- ARDPA MQGTHW 34 20 8 18949 18 30 VDAIP PLT MLDY ADI- 302 VH4- VK3-ATAWT QLRGHWP 85 13 2 18950 39 11 FDH PTIT ADI- 303 VH3- VL2- AKDGLSSYRNGN 5 19 16 18951 23 14 RDVSR ALGV VYYID V ADI- 304 VH3- VL2- AKDGLSSYRNGN 5 18 11 18952 23 14 RDLSR TLGV VYYID V ADI- 305 VH1- VK3- ARDAYQQYGSSF 21 12 11 18953 69 20 EVWTG LT SYLPPF DY ADI- 306 VH3- VK3- ARAPYQQYSIWP 16 11 6 18955 30 15 DIWSG QT YCLDY ADI- 307 VH1- VL2- ATRLYCSYAGRYI 89 23 10 18956 69 11 TLGSPF YV DN ADI- 308 VH3- VL1- ARVHVQSYDSSLS 78 12 3 18957 21 40 DLVTTI GAI FGVDF DF ADI- 309 VH1- VK2-AREPPS MQGTQW 51 18 3 18958 18 30 DDAAR PVT LFDY ADI- 310 VH1- VK1-ATPTPV QQTYIIPY 88 18 4 18959 24 39 GATDF T ADI- 311 VH4- VL3- AREGPQVWDTSS 50 15 5 18960 39 21 NWELL DHVV NAFDI ADI- 312 VH3- VL1- ARVSTEQSYDSSLS 80 1 0 18962 21 40 LGYYY W MDV ADI- 313 VH1-3 VK4-1 GRDWDQQYYGNF 91 14 9 18965 GAIRVL PT DY ADI- 314 VH3- VK2- ARDPG MQGTHW 35 133 18966 30 30 VGSYY PPT NWGM DV ADI- 315 VH1- VK1- ATPLPA QQTYIIPY 88 2312 18967 24 39 GALDK T ADI- 316 VH4- VK3- TRDLG QQRTNWP 93 17 8 18968304 11 YSTSSP IT SFYYG MDV ADI- 317 VHl- VK2- ARDVF MQATDW 43 15 4 1896918 30 SKTAA PVT RIFDY ADI- 318 VH4- VK3- ARDIGY QQRTNWI 26 6 9 18970 30411 GDHGT T GSYYY GIED ADI- 319 VH3- VL3- AKDRV QVWDSRS 6 17 12 18971 2321 GWFGE EHVI FDAFDF ADI- 320 VH1- VK2- ARDPA MQGTHW 34 20 8 18972 18 30VDAIP PLT MLDY ADI- 321 VH2- VK3- ALMRP QLYHRSP 13 18 14 18973 70 20FWSRD GSASQTV DYYYSI WT AV ADI- 322 VH1- VK2- ARDTP MQGIFRP 41 22 518974 18 30 ATAAP GT LLDY ADI- 323 VH1- VK2- ARDSG MQATEFP 40 11 3 1897518 24 CCSGST PMYT SDV ADI- 324 VH4- VK1- ARDNK QQSYTTR 33 5 9 18976 3139 HHDSG LT NYYAY FDH ADI- 325 VH1-3 VK1- ARQVS QQYDNLP 68 17 6 18977 33TSGWH LT ATSHRF AP ADI- 326 VH3- VK1-5 AKSSSS QQYYNW 11 9 11 18978 30HVNSR WT QDK ADI- 327 VH1- VK2- ARDSFS MQATHRP 39 11 1 18979 18 30ETGTGF RT PDF ADI- 328 VH5- VK3- AKSNV QEVRNWP 10 8 9 18980 51 11 GNTGWPCT NY ADI- 329 VH4- VK3- ARCGN QQYGSSP 17 27 9 18981 30 20 EYGEV WTHPFDI ADI- 330 VH1- VK2- ARDSFS MQATHRP 39 7 1 18982 18 30 ETGTGF RT PDFADI- 331 VH3- VK1- AREAY LQHNRYP 49 14 5 18983 30 17 EEWEL FT TMGNL DHADI- 332 VH4- VK1- ARGEH QQANSFP 56 29 5 18984 61 12 FAYWW RT GN ADI-333 VH1-2 VK1- TSQTSP QQTYNGL 95 22 16 18985 39 YTPGA IA MGV ADI- 334VH3- VL1- ARGAS QSYDSLS 54 12 5 18986 30 40 YYYVS ASWV SDLGY ADI- 335VH1- VK3- ARDAY QQYGSSF 20 12 8 18987 69 20 EVWTG LT SYLPPF DD ADI- 336VH3- VL1- VREAY QSYDSSLS 97 22 6 18988 21 40 ASSSAL GWV YWFDP ADI- 337VH3- VK2- ARSLGS MQALQTP 71 14 6 18989 48 28 GNYDN YT EDQTF YYYYG MDVADI- 338 VH4- VK3- ARDLG QQRSNWP 28 19 6 18990 304 11 TANNY PYT YFGMD VADI- 339 VH4- VL3- ASGPV QVWDSST 81 22 14 18991 304 21 GMATS DYHVV NWFDPADI- 340 VH1- VL1- ARAPS QSYDSSLS 15 14 7 18992 46 40 HDEWV AWV AISRNVVGFDA ADI- 341 VH3- VL1- AREVLP QSYDISLS 53 10 7 18993 21 40 ATAIGG ASYVAWLDP ADI- 342 VH1- VL2- ARIGHV CSYVAGS 58 13 7 18994 18 23 TAVAG TSVAPPDY ADI- 343 VH4- VL3- ASGPV QVWDSGT 81 18 12 18995 304 21 GMATS DYHVVNWFDP ADI- 344 VH1-2 VL1- ARSSLV GTWDASL 72 17 10 18996 51 GASPNF SAAMVDF ADI- 345 VH4- VK3- ARVHP QQYAYWP 77 16 9 18997 34 15 SYDFG PYT WRFFDF ADI- 346 VH4- VL3- ASGPV QVWDSST 81 15 15 18998 304 21 GMATS DHHVVNWFDP ADI- 347 VH1- VL2- ARPNY CSYAGGL 65 13 3 18999 69 11 DILTGY YVAFDI ADI- 348 VH1-8 VL1- VQMDH AAWDDSL 96 10 6 19000 36 CRSTSC NVWVSEGNW FDT ADI- 349 VH3- VL2-8 TRQDD SSYAGSN 94 10 7 19001 49 FWSGH DLGVPYYFEY ADI- 350 VH4- VK1- ARQFG QQSYSIPW 66 17 8 19002 59 39 YDKNT TLSRLDF DY ADI- 351 VH4- VL3- AREGP QVWDTSS 50 15 4 19003 39 21 NWELLDHVV NAFDI ADI- 352 VH1- VK2- ARDPP MQGTHGR 36 19 7 19004 18 30 ASAAAGIS MLDY ADI- 353 VH1- VK1- ASQSSP QLNSGAL 82 21 9 19005 18 39 YTPGA FTMGV ADI- 354 VH3- VK3- ARAKT QRYGNSW 14 30 12 19006 11 20 SYYFY P ALDVADI- 355 VH3- VK4-1 AKESL HQYYDTH 8 18 5 19007 23 DFGSGS T YNWFD T ADI-356 VH3- VK3- ARDPSL QQRSNWP 37 15 6 19008 30 11 GYNNH PMYS YFDY ADI-357 VH1- VK3- ARDAY QQYGSSF 21 19 6 19009 69 20 EVWTG LT SYLPPF DY ADI-358 VH3- VL1- ARDVQ QSYDSSLS 47 0 0 19010 21 40 YSGYD ALYV SGYYF DY ADI-359 VH3- VL4- ATIRGI EAWDFNT 87 19 9 19011 30 60 VAGLC GGV DN ADI- 360VH4-4 VK1- ARLSG QQSYNTV 63 12 10 19012 39 NCSGG YT SCYSPF DH ADI- 361VH5- VK1- ARPMT QQTNSFLP 64 4 2 19013 51 12 TQEGF LT DL ADI- 362 VH4-VK3- ARSADI QQYGTSP 70 21 10 19014 304 20 DIVWG WT SSLYMP L ADI- 363VH3- VL1- ARIGYS QSYDKSL 59 13 5 19016 21 40 SAHHY SGGYV QYYMD V ADI-364 VH1- VL3- ASQSSP QSADSSG 82 22 0 19017 18 25 YTPGA TYPW MGV

TABLE 3 Affinity and Neutralization data for anti-RSV antibodies NeatNeat IC₅₀ IC₅₀ Antibody Prefusion Postfusion Prefusion Postfusion(ug/ml) (ug/ml) number subtype A K_(D) subtype A K_(D) subtype B subtypeB subtype subtype Name (Ab #) (M)* (M)* K_(D) (M)* K_(D) (M)* A* B* ADI-232 7.36E−10 NB 7.64E−10 NB 0.040 0.035 18875 ADI- 233 7.07E−10 1.71E−093.16E−10 1.79E−10 0.037 0.179 18876 ADI- 234 3.03E−10 NB 3.83E−10 NB0.410 0.130 18877 ADI- 235 4.53E−09 4.83E−10 5.82E−09 3.88E−10 >10 8.30818878 ADI- 236 3.12E−10 NB 3.58E−10 NB 0.041 0.103 18879 ADI- 2372.55E−10 NB 3.04E−10 NB 0.041 0.055 18880 ADI- 238 4.27E−10 NB 4.76E−10NB 0.041 0.057 18882 ADI- 239 4.31E−10 NB 5.66E−10 NB 0.041 0.050 18883ADI- 240 3.38E−10 NB 2.04E−10 NB 0.073 0.239 18884 ADI- 241 2.18E−093.84E−10 3.89E−09 3.07E−10 0.376 8.635 18885 ADI- 242 NB 7.43E−101.22E−08 5.49E−10 1.110 >10 18887 ADI- 243 NB 2.54E−08 NB1.16E−09 >10 >10 18888 ADI- 244 5.54E−10 NB 5.87E−10 NB 0.040 0.01918889 ADI- 245 4.89E−10 NB 4.58E−10 NB 0.041 0.041 18890 ADI- 2465.34E−10 NB 5.13E−10 NB 0.012 0.026 18891 ADI- 247 2.17E−10 NB 2.53E−10NB 0.018 0.117 18892 ADI- 248 2.45E−10 NB 2.78E−10 NB 0.123 0.182 18893ADI- 249 2.54E−09 NB 3.27E−10 NB 0.345 0.123 18894 ADI- 250 NB 2.37E−09NB 4.86E−10 2.303 >10 18895 ADI- 251 2.27E−09 2.79E−10 1.81E−09 2.70E−101.100 4.722 18896 ADI- 252 1.47E−09 2.19E−10 1.53E−09 1.85E−10 0.2880.762 18897 ADI- 253 3.05E−10 NB 3.25E−10 NB 0.030 0.097 18898 ADI- 2541.92E−09 2.66E−10 1.59E−09 2.51E−10 0.742 2.700 18899 ADI- 255 1.19E−09NB 3.31E−10 NB 0.035 0.059 18900 ADI- 256 2.17E−09 NB NB NB 5.646 5.76218901 ADI- 257 1.07E−10 NB 1.01E−10 NB 0.024 0.150 18902 ADI- 2583.24E−10 NB 2.72E−10 NB 0.036 0.118 18903 ADI- 259 2.51E−10 NB 2.37E−10NB 0.018 0.089 18904 ADI- 260 3.38E−09 NB NB NB 0.685 3.676 18905 ADI-261 NB 2.33E−08 NB 1.10E−09 >10 >10 18906 ADI- 262 1.74E−10 NB 2.04E−10NB 3.300 >10 18907 ADI- 263 3.02E−10 NB 3.52E−10 NB 0.018 0.095 18908ADI- 264 5.08E−10 5.81E−10 2.88E−10 2.25E−10 0.110 0.169 18909 ADI- 2654.67E−09 NB 1.06E−08 NB >10 0.767 18910 ADI- 266 NB 3.53E−10 NB 2.80E−100.301 4.853 18911 ADI- 267 2.58E−10 NB 2.86E−10 NB 0.024 0.061 18912ADI- 268 5.68E−10 NB 4.71E−10 NB <0.01 <0.01 18913 ADI- 269 2.81E−08 NB4.21E−10 NB 1.199 0.021 18915 ADI- 270 5.85E−10 NB 4.65E−10 NB <0.01<0.01 18916 ADI- 271 3.56E−10 NB 3.32E−10 NB 0.024 0.091 18917 ADI- 272NB 5.67E−10 NB 4.09E−10 0.377 4.590 18918 ADI- 273 2.02E−10 NB 1.63E−10NB 0.123 0.261 18919 ADI- 274 6.78E−10 NB 9.77E−11 NB 0.041 0.049 18920ADI- 275 5.75E−09 NB NB NB 1.703 1.172 18921 ADI- 276 3.47E−09 3.22E−105.27E−09 2.87E−10 >10 5.051 18922 ADI- 277 5.17E−10 NB 1.79E−09 NB 0.0780.147 18923 ADI- 278 6.48E−09 4.11E−10 NB 3.21E−10 0.572 1.073 18924ADI- 279 4.99E−09 NB NB NB >10 >10 18925 ADI- 280 2.52E−10 NB 2.50E−10NB 0.023 0.092 18926 ADI- 281 3.58E−09 NB 2.99E−09 NB 0.022 0.067 18927ADI- 282 4.49E−10 NB 5.15E−10 NB 0.034 0.062 18928 ADI- 283 1.61E−09 NBNB NB 0.261 0.369 18929 ADI- 284 3.87E−10 NB 3.72E−10 NB 0.013 0.05118930 ADI- 285 5.65E−10 NB 4.88E−10 NB >10 >10 18931 ADI- 286 9.17E−10NB 1.39E−09 NB 0.184 0.351 18932 ADI- 287 NB 2.00E−08 NB 6.16E−10 0.0750.137 18933 ADI- 288 6.60E−10 NB 5.82E−10 NB 0.779 0.355 18935 ADI- 2893.03E−10 NB 2.98E−10 NB 0.032 0.035 18936 ADI- 290 2.89E−10 NB 2.73E−10NB 0.084 0.508 18937 ADI- 291 1.65E−10 2.16E−10 1.50E−10 1.68E−10 0.8374.255 18938 ADI- 292 5.74E−10 NB 5.60E−10 NB 0.018 0.038 18939 ADI- 2931.12E−09 NB 1.56E−09 NB 0.023 0.063 18940 ADI- 294 NB 1.91E−08 NB6.45E−10 >10 >10 18941 ADI- 295 8.65E−10 2.81E−10 5.12E−10 2.58E−100.374 0.614 18942 ADI- 296 6.46E−10 NB 7.25E−10 NB 0.027 0.043 18943ADI- 297 3.09E−10 NB 3.37E−10 NB 0.026 0.074 18944 ADI- 298 1.58E−102.06E−10 1.57E−10 1.66E−10 0.093 0.227 18946 ADI- 299 2.45E−09 2.96E−102.20E−09 2.82E−10 1.299 3.602 18947 ADI- 300 4.55E−09 2.57E−10 2.10E−092.47E−10 1.123 4.346 18948 ADI- 301 3.07E−10 NB 3.08E−10 NB 0.040 0.07618949 ADI- 302 1.13E−09 3.93E−10 4.18E−09 3.85E−10 >10 >10 18950 ADI-303 7.52E−10 1.29E−09 5.35E−09 1.13E−09 3.398 >10 18951 ADI- 3047.15E−10 7.29E−10 1.01E−09 6.33E−10 1.589 2.745 18952 ADI- 305 5.13E−10NB 4.21E−10 NB 0.034 0.022 18953 ADI- 306 5.99E−10 2.56E−10 2.37E−092.50E−10 1.933 3.116 18955 ADI- 307 1.82E−10 NB 2.24E−10 NB >10 >1018956 ADI- 308 4.69E−10 NB 3.24E−10 NB 1.339 6.084 18957 ADI- 3092.86E−10 NB 3.02E−10 NB 0.587 3.364 18958 ADI- 310 4.68E−09 NB NB NB7.214 2.258 18959 ADI- 311 1.78E−10 NB 1.83E−10 NB 0.034 0.107 18960ADI- 312 8.83E−09 NB 2.28E−08 NB 4.439 >10 18962 ADI- 313 NB NB NB 3.0236.892 18965 ADI- 314 5.78E−10 NB 5.62E−10 NB 0.044 0.130 18966 ADI- 3158.09E−10 NB NB NB 6.737 3.651 18967 ADI- 316 1.98E−09 4.38E−10 6.02E−103.05E−10 0.909 0.541 18968 ADI- 317 3.03E−10 NB 2.97E−10 NB 0.035 0.18718969 ADI- 318 1.04E−08 6.84E−09 4.45E−10 4.12E−10 >10 0.333 18970 ADI-319 1.57E−10 NB 1.68E−10 NB 0.039 0.114 18971 ADI- 320 2.98E−10 NB3.68E−10 NB 0.016 0.107 18972 ADI- 321 3.78E−09 4.95E−10 2.63E−093.94E−10 9.605 6.273 18973 ADI- 322 2.53E−10 NB 2.90E−10 NB 0.030 0.10518974 ADI- 323 2.67E−10 NB 2.98E−10 NB 0.037 0.174 18975 ADI- 3244.03E−09 2.36E−09 1.24E−09 2.09E−10 6.290 10.600 18976 ADI- 325 7.86E−10NB 9.66E−10 NB 0.108 0.117 18977 ADI- 326 3.00E−09 NB NB NB >10 >1018978 ADI- 327 1.89E−10 NB 1.84E−10 NB 0.012 0.031 18979 ADI- 328 NB5.33E−10 NB 3.50E−10 3.599 >10 18980 ADI- 329 1.53E−09 3.53E−10 1.15E−092.80E−10 >10 >10 18981 ADI- 330 1.92E−10 7.65E−10 1.95E−10 7.47E−100.018 0.053 18982 ADI- 331 1.71E−09 NB 5.81E−10 NB 0.028 0.075 18983ADI- 332 1.29E−08 8.03E−10 6.08E−09 6.59E−10 >10 >10 18984 ADI- 3335.66E−10 NB 1.70E−09 NB 0.034 0.090 18985 ADI- 334 2.68E−09 NB 2.38E−10NB 0.464 0.123 18986 ADI- 335 4.49E−10 NB 5.24E−10 NB 0.015 0.027 18987ADI- 336 2.93E−10 NB 3.70E−10 NB 0.089 0.370 18988 ADI- 337 3.51E−093.56E−10 3.92E−09 3.77E−10 >10 >10 18989 ADI- 338 8.90E−10 2.94E−104.91E−10 2.52E−10 0.580 0.845 18990 ADI- 339 1.35E−10 1.52E−10 0.0280.228 18991 ADI- 340 7.66E−10 1.53E−09 9.69E−10 9.07E−10 2.546 5.69218992 ADI- 341 2.55E−10 NB 2.77E−10 NB 0.078 0.128 18993 ADI- 3423.10E−10 NB 3.31E−10 NB 0.047 0.108 18994 ADI- 343 1.20E−10 1.23E−081.27E−10 0.043 0.125 18995 ADI- 344 2.52E−09 NB 3.60E−09 NB >10 >1018996 ADI- 345 5.01E−09 NB 5.32E−09 NB >10 >10 18997 ADI- 346 1.57E−101.24E−08 1.72E−10 NB 0.055 0.458 18998 ADI- 347 5.92E−10 1.67E−101.02E−09 1.41E−10 1.805 6.465 18999 ADI- 348 1.10E−10 1.75E−10 1.04E−101.28E−10 0.037 0.129 19000 ADI- 349 1.07E−09 1.93E−10 1.06E−091.49E−10 >10 3.259 19001 ADI- 350 1.63E−09 NB NB NB 2.886 4.507 19002ADI- 351 1.61E−10 NB 1.68E−10 NB 0.047 0.125 19003 ADI- 352 2.28E−10 NB2.73E−10 NB 0.020 0.128 19004 ADI- 353 9.63E−10 NB 9.64E−10 NB 0.0410.110 19005 ADI- 354 1.75E−09 NB NB NB 4.891 5.059 19006 ADI- 3556.18E−10 9.69E−10 6.08E−10 4.57E−10 0.208 0.370 19007 ADI- 356 3.63E−09NB NB NB 8.293 >10 19008 ADI- 357 4.42E−10 NB 4.66E−10 NB 0.062 0.06619009 ADI- 358 6.04E−09 NB 2.84E−09 NB >10 0.650 19010 ADI- 359 2.15E−09NB NB NB >10 6.237 19011 ADI- 360 2.89E−09 3.04E−10 1.14E−093.14E−10 >10 >10 19012 ADI- 361 NB 1.61E−08 NB 5.83E−10 9.504 >10 19013ADI- 362 2.82E−09 3.59E−10 2.21E−09 2.77E−10 1.745 >10 19014 ADI- 363 NBNB NB NB 0.052 0.092 19016 ADI- 364 1.10E−08 NB 7.20E−09 NB 1.562 0.79519017 *NN; non-neutralizing, NB; non-binding, ND; not determined. IgGKDs were calculated for antibodies with BLI binding responses >0.1 nm.Antibodies with BLI binding responses <0.05 nm were designated as NB.

TABLE 4 Bin, patch, and antigenic site assignments for anti-RSVantibodies Antibody Antigenic number Bin Patch Site Name (Ab #)Assignment Assignment Assignment ADI-18875 232 D25 1, 2 Ø ADI-18876 233Mota 5 II ADI-18877 234 D25/mota/MPE8 4 V ADI-18878 235 101F/13390ADI-18879 236 D25/mota/MPE8 4 V ADI-18880 237 D25/mota/MPE8 4 VADI-18882 238 D25 1, 2 Ø ADI-18883 239 D25 4 V ADI-18884 240 14469 IADI-18885 241 101F/13390 ADI-18887 242 Mota/13390 ADI-18888 243Mota/101F/13390 ADI-18889 244 D25 1, 2 Ø ADI-18890 245 D25 2 Ø ADI-18891246 D25 2, 1 Ø ADI-18892 247 Mota/MPE8 4 V ADI-18893 248 Mota/MPE8 IIIADI-18894 249 D25 ADI-18895 250 Unknown ADI-18896 251 101F/13390ADI-18897 252 Mota/101F/13390 III ADI-18898 253 D25/mota/MPE8 4 VADI-18899 254 101F/13390 I ADI-18900 255 D25 1 Ø ADI-18901 256 UnknownADI-18902 257 14443 9 IV ADI-18903 258 D25/mota/MPE8 4, 3 V ADI-18904259 D25/mota/MPE8 4 V ADI-18905 260 MPE8 ADI-18906 261 Mota/101F/13390ADI-18907 262 UK ADI-18908 263 Mota/MPE8 III ADI-18909 264 Mota 5 IIADI-18910 265 Unknown ADI-18911 266 Mota ADI-18912 267 Mota/MPE8 IIIADI-18913 268 D25 1 Ø ADI-18915 269 D25/mota ADI-18916 270 D25 1 ØADI-18917 271 Mota/MPE8 III ADI-18918 272 Mota ADI-18919 273 UKADI-18920 274 101F 9 IV ADI-18921 275 101F ADI-18922 276 Mota ADI-18923277 Mota/MPE8/101F III ADI-18924 278 Unknown ADI-18925 279 101FADI-18926 280 D25/mota/MPE8 4 V ADI-18927 281 D25/mota ADI-18928 282 D251, 2 Ø ADI-18929 283 101F 1 UK ADI-18930 284 D25 1, 2 Ø ADI-18931 285101F IV ADI-18932 286 Mota 5 II ADI-18933 287 Unknown ADI-18935 288 Mota6, 5 III ADI-18936 289 D25/mota 4 V ADI-18937 290 Mota 5 II ADI-18938291 Mota/101F III ADI-18939 292 D25 9 Ø ADI-18940 293 D25/mota 1, 2 VADI-18941 294 Mota ADI-18942 295 Mota II ADI-18943 296 D25 5 UKADI-18944 297 D25/mota/MPE8 1, 2 V ADI-18946 298 101F 4 IV ADI-18947 299101F/13390 ADI-18948 300 101F/13390 ADI-18949 301 D25/mota/MPE8 4 VADI-18950 302 13390 I ADI-18951 303 Mota/13390 III ADI-18952 304Mota/13390 III ADI-18953 305 D25 2 Ø ADI-18955 306 101F/13390 IADI-18956 307 14469 I ADI-18957 308 Mota/MPE8 III ADI-18958 309 Mota 4 VADI-18959 310 14443 ADI-18960 311 14469 9 IV ADI-18962 312 Mota/MPE8ADI-18965 313 Unknown ADI-18966 314 D25/mota/MPE8 4 V ADI-18967 315 101F9 IV ADI-18968 316 Mota 5 II ADI-18969 317 D25/mota/MPE8 4 V ADI-18970318 Mota/MPE8 ADI-18971 319 14469 9 IV ADI-18972 320 D25/mota/MPE8 4 VADI-18973 321 13390 ADI-18974 322 D25/mota/MPE8 4 V ADI-18975 323D25/mota/MPE8 4 V ADI-18976 324 13390 ADI-18977 325 D25/mota 4 VADI-18978 326 14469 ADI-18979 327 Mota/MPE8 4 V ADI-18980 328 MotaADI-18981 329 101F/13390 I ADI-18982 330 Mota/MPE8 4 V ADI-18983 331101F 3, 9 Q ADI-18984 332 13390 ADI-18985 333 D25/mota 4 V ADI-18986 334D25 ADI-18987 335 D25 Ø ADI-18988 336 Mota/MPE8 III ADI-18989 337101F/13390 ADI-18990 338 Mota 5 II ADI-18991 339 14443 9 IV ADI-18992340 101F IV ADI-18993 341 Mota/MPE8 III ADI-18994 342 Mota/MPE8 IIIADI-18995 343 14443 IV ADI-18996 344 Unknown ADI-18997 345 D25/motaADI-18998 346 14443 9 IV ADI-18999 347 101F 9 IV ADI-19000 348 14443 9IV ADI-19001 349 101F/13390 I ADI-19002 350 Unknown UK ADI-19003 35114469 9 IV ADI-19004 352 D25/mota/MPE8 4 V ADI-19005 353 D25/mota VADI-19006 354 Unknown UK ADI-19007 355 Mota/MPE8 5 II ADI-19008 356Unknown ADI-19009 357 D25 1 Ø ADI-19010 358 Mota/MPE8 ADI-19011 359Unknown ADI-19012 360 13390 ADI-19013 361 Unknown ADI-19014 362101F/13390 ADI-19016 363 Mota/MPE8 ADI-19017 364 D25/mota

TABLE 5 A subset of anti-RSV F antibodies cross-neutralize humanmetapneumovirus. Antibody Prefusion Postfusion RSV F number HMPV-A1RSV-A2 IC₅₀ RSV F K_(D) RSV F K_(D) Binding Name (Ab#) IC₅₀ (μg/ml)(μg/ml) (M) (M) Site ADI- 6.1 2.5 7.6 × 10⁻¹⁰ 1.5 × 10⁻⁹ IV* 18992 MPE8N/A 0.07 0.04 — — — Control N/A, not applicable *Binding site assignmentbased on competition only.

Materials and Methods Study Design

To profile the antibody response to RSV F, peripheral blood mononuclearcells were obtained from a adult donor approximately between 20-35 yearsof age, and monoclonal antibodies from RSV F-reactive B cells wereisolated therefrom. The antibodies were characterized by sequencing,binding, epitope mapping, and neutralization assays. All samples forthis study were collected with informed consent of volunteers. Thisstudy was unblinded and not randomized. At least two independentexperiments were performed for each assay.

Generation of RSV F Sorting Probes

The soluble prefusion and postfusion probes were based on the RSV F ΔFPand DS-Cav1 constructs that we previously crystallized and determined tobe in the pre- and postfusion conformations, respectively (11, 15). Toincrease the avidity of the probes and to uniformly orient the RSV Fproteins, the trimeric RSV F proteins were coupled to tetramericstreptavidin through biotinylation of a C-terminal AviTag. For eachprobe, both a C-terminal His-Avi tagged version and a C-terminalStrepTagII version were co-transfected into FreeStyle 293-F cells. Thesecreted proteins were purified first over Ni-NTA resin to removetrimers lacking the His-Avi tag. The elution from the Ni-NTApurification was then purified over Strep-Tactin resin. Due to the lowavidity of a single StrepTagII for the Strep-Tactin resin, additionalwashing steps were able to remove singly StrepTagged trimers. Thisresulted in the purification of trimers containing two StrepTagII taggedmonomers and therefore only one His-Avi tagged monomer. Thispurification scheme results in a single AviTag per trimer which greatlyreduces the aggregation or ‘daisy-chaining’ that occurs when trimericproteins containing three AviTags are incubated with tetramericstreptavidin. RSV F trimers were biotinylated using biotin ligase BirAaccording to the manufacturer's instructions (Avidity, LLC).Biotinylated proteins were separated from excess biotin bysize-exclusion chromotography on a Superdex 200 column (GE Healthcare).Quantification of the number of biotin moieties per RSV F trimer wasperformed using the Quant*Tag Biotin Kit per the manufacturer'sinstructions (Vector Laboratories).

Single B-Cell Sorting

Peripheral blood mononuclear cells were stained using anti-human IgG(BV605), IgA (FITC), CD27 (BV421), CD8 (PerCP-Cy5.5), CD14(PerCP-Cy5.5), CD19 (PECy7), CD20 (PECy7) and a mixture of dual-labeledDS-Cav1 and F ΔFP tetramers (50 nM each). Dual-labeled RSV F tetramerswere generated by incubating the individual AviTagged RSV F proteinswith premium-grade phycoerythrin-labeled streptavidin (Molecular Probes)or premium-grade allophycocyanin-labeled streptavidin for at least 20minutes on ice at a molar ratio of 4:1. Tetramers were prepared freshfor each experiment. Single cells were sorted on a BDfluorescence-activated cell sorter Aria II into 96-well PCR plates(BioRad) containing 20 μL/well of lysis buffer [5 μL of 5×first strandcDNA buffer (Invitrogen), 0.25 μL RNaseOUT (Invitrogen), 1.25 μLdithiothreitol (Invitrogen), 0.625 μL NP-40 (New England Biolabs), and12.6 μL dH₂O]. Plates were immediately frozen on dry ice before storageat −80° C.

Amplification and Cloning of Antibody Variable Genes

Single B cell PCR was performed as described previously (22). Briefly,IgH, Igλ and Igκ variable genes were amplified by RT-PCR and nested PCRreactions using cocktails of IgG and IgA-specific primers (22). Theprimers used in the second round of PCR contained 40 base pairs of 5′and 3′ homology to the cut expression vectors to allow for cloning byhomologous recombination into Saccharomyces cerevisiae (40). PCRproducts were cloned into S. cerevisiae using the lithium acetate methodfor chemical transformation (41). Each transformation reaction contained20 μL of unpurified heavy chain and light chain PCR product and 200 ngof cut heavy and light chain plasmids. Following transformation,individual yeast colonies were picked for sequencing andcharacterization.

Expression and Purification of IgGs and Fab Fragments

Anti-RSV F IgGs were expressed in S. cerevisiae cultures grown in24-well plates, as described previously (23). Fab fragments used forcompetition assays were generated by digesting the IgGs with papain for2 h at 30° C. The digestion was terminated by the addition ofiodoacetamide, and the Fab and Fc mixtures were passed over Protein Aagarose to remove Fc fragments and undigested IgG. The flowthrough ofthe Protein A resin was then passed over CaptureSelect™ IgG-CH1 affinityresin (ThermoFischer Scientific), and eluted with 200 mM acetic acid/50mM NaCl pH 3.5 into ⅛th volume 2M Hepes pH 8.0. Fab fragments then werebuffer-exchanged into PBS pH 7.0.

Biolayer Interferometry Binding Analysis

IgG binding to DS-Cav1 and FΔ FP was determined by BLI measurementsusing a ForteBio Octet HTX instrument (Pall Life Sciences). Forhigh-throughput K_(D) screening, IgGs were immobilized on AHQ sensors(Pall Life Sciences) and exposed to 100 nM antigen in PBS containing0.1% BSA (PBSF) for an association step, followed by a dissociation stepin PBSF buffer. Data was analyzed using the FortéBio Data AnalysisSoftware 7. The data was fit to a 1:1 binding model to calculate anassociation and dissociation rate, and K_(D) was calculated using theratio k_(d)/k_(a).

Antibody Competition Assays

Antibody competition assays were performed as previously described (23).Antibody competition was measured by the ability of a control anti-RSV FFab to inhibit binding of yeast surface-expressed anti-RSV F IgGs toeither DS-Cav1 or FΔ FP. 50 nM biotinylated DS-Cav1 or FΔ FP waspre-incubated with 1 μM competitor Fab for 30 min at room temperatureand then added to a suspension of yeast expressing anti-RSV F IgG.Unbound antigen was removed by washing with PBS containing 0.1% BSA(PBSF). After washing, bound antigen was detected using streptavidinAlexa Fluor 633 at a 1:500 dilution (Life Technologies) and analyzed byflow cytometry using a FACSCanto II (BD Biosciences). The level ofcompetition was assessed by measuring the fold reduction in antigenbinding in the presence of competitor Fab relative to an antigen-onlycontrol. Antibodies were considered competitors when a greater thanfive-fold reduction was observed in the presence of control Fab relativeto an antigen-only control.

Expression, Purification and Biotinylation of preF Patch Variants

A panel of 9 patches of 2-4 mutations uniformly covering the surface ofthe preF molecule was designed based on the structure of prefusion RSV F(10). For known antigenic sites, including those recognized bymotavizumab, 101F, D25, AM14 and MPE8, patches incorporated residuesassociated with viral escape or known to be critical for antibodybinding. Residues with high conservation across 184 subtype A, subtype Band bovine RSV F sequences were avoided where possible to minimize thelikelihood of disrupting protein structure. The mutations present ineach patch variant are shown in FIG. 7A. Mutations for each patchvariant were cloned into the prefusion stabilized RSV F (DS-Cav1)construct with a C-terminal AviTag for site specific biotinylation.Proteins were secreted from FreeStyle 293-F cells, purified over Ni-NTAresin and biotinylated using biotin ligase BirA according to themanufacturer's instructions (Avidity, LLC). Biotinylated proteins wereseparated from excess biotin by size-exclusion chromotography on aSuperdex 200 column (GE Healthcare). A deglycosylated version of DS-Cav1was produced by expressing DS-Cav1 in the presence of 1 μM kifunensineand digesting with 10% (wt/wt) EndoH before biotinylation.

Luminex Assay for Patch Variant Binding

Binding of isolated antibodies to the patch variants was determinedusing a high-throughput Luminex assay. Each biotinylated variant and aDS-Cav1 control were coupled to avidin coated MagPlex beads (Bio-Rad),each with a bead identification number reflecting a unique ratio of redand infrared dyes embedded within the bead. The coupled beads were thenmixed with a six-fold serial dilution of each antibody, ranging from 400nM to 1.4 μM, in a 384-well plate. Beads were washed using a magneticmicroplate washer (BioTek) before incubation with a PE conjugated mouseanti-human IgG Fc secondary antibody (Southern Biotech). Beads wereclassified and binding of PE was measured using a FLEXMAP 3D flowcytometer (Luminex).

RSV Neutralization Assays

Viral stocks were prepared and maintained as previously described (61).Recombinant mKate-RSV expressing prototypic subtype A (strain A2) andsubtype B (18537) F genes and the Katushka fluorescent protein wereconstructed as reported by Hotard et al. (62). HEp-2 cells weremaintained in Eagle's minimal essential medium containing 10% fetalbovine serum supplemented with glutamine, penicillin and streptomycin.Antibody neutralization was measured by a fluorescence plate readerneutralization assay (15). A 30 μL solution of culture media containing2.4×10⁴ HEp-2 cells was seeded in 384-well black optical bottom plate(Nunc, Thermo Scientific). IgG samples were serially diluted four-foldfrom 1:10 to 1:163840 and an equal volume of recombinant mKate-RSV A2was added. Samples were mixed and incubated at 37° C. for one hour.After incubation, 50 μL mixture of sample and virus was added to cellsin 384-well plate, and incubated at 37° C. for 22-24 hours. The assayplate was then measured for fluorescence intensity in a microplatereader at Ex 588 nm and Em 635 nm (SpectraMax Paradigm, moleculardevices). IC₅₀ of neutralization for each sample was calculated by curvefitting using Prism (GraphPad Software Inc.).

Human Metapneumovirus Neutralization Assays

Predetermined amounts of GFP-expressing hMPV recombinant virus (NL/1/00,A1 sublineage, a kind gift of Bernadette van den Hoogen and RonFouchier, Rotterdam, the Netherlands) were mixed with serial dilutionsof monoclonal antibodies before being added to cultures of Vero-118cells growing in 96-well plates with Dulbecco's Modified Eagle's mediumsupplemented with 10% fetal calf serum. Thirty-six hours later, themedium was removed, PBS was added and the amount of GFP per well wasmeasured with a Tecan microplate reader M200. Fluorescence values wererepresented as percent of a virus control without antibody.

Polyreactivity Assay

Antibody polyreactivity was assessed using a previously describedhigh-throughput assay that measures binding to solubilized CHO cellmembrane preparations (SMPs) (43). Briefly, two million IgG-presentingyeast were transferred into a 96-well assay plate and pelleted to removethe supernatant. The pellet was resuspended in 50 μL of 1:10 dilutedstock b-SMPs and incubated on ice for 20 minutes. Cells were then washedtwice with ice-cold PBSF and the cell pellet was re-suspended in 50 μLof secondary labeling mix (Extravidin-R-PE, anti-human LCFITC, andpropidium iodide). The mix was incubated on ice for 20 minutes followedby two washes with ice-cold PBSF. Cells were then re-suspended in 100 μLof ice-cold PBSF, and the plate was run on a FACSCanto II (BDBiosciences) using a HTS sample injector. Flow cytometry data wasanalyzed for mean fluorescence intensity in the R-PE channel andnormalized to proper controls in order to assess non-specific binding.

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Heavy chain variable region (“HC”) nucleic acid sequence

Heavy chain variable region (“HC”) amino acid sequence

Heavy chain variable region CDR H1 (“H1”) amino acid sequence

Heavy chain variable region CDR H1 (“H1”) nucleic acid sequence

Heavy chain variable region CDR H2 (“H2”) amino acid sequence

Heavy chain variable region CDR H2 (“H2”) nucleic acid sequence

Heavy chain variable region CDR H3 (“H3”) amino acid sequence

Heavy chain variable region CDR H3 (“H3”) nucleic acid sequence

Light chain variable region (“LC”) nucleic acid sequence

Light chain variable region (“LC”) amino acid sequence

Light chain variable region CDR L1 (“L1”) amino acid sequence

Light chain variable region CDR Li (“Li”) nucleic acid sequence

Light chain variable region CDR L2 (“L2”) amino acid sequence

Light chain variable region CDR L2 (“L2”) nucleic acid sequence

Light chain variable region CDR L3 (“L3”) amino acid sequence

Light chain variable region CDR L3 (“L3”) nucleic acid sequence

The informal sequence listing for antibodies 365-372 provides thefollowing ten (10) sequence elements contained in each of the 8antibodies, identified as described above and designated as AntibodyNumbers (Ab #) 365 through 372, in the following order:

Heavy chain variable region (“HC”) nucleic acid sequence

Heavy chain variable region (“HC”) amino acid sequence

Heavy chain variable region CDR H1 (“H1”) amino acid sequence

Heavy chain variable region CDR H2 (“H2”) amino acid sequence

Heavy chain variable region CDR H3 (“H3”) amino acid sequence

Light chain variable region (“LC”) nucleic acid sequence

Light chain variable region (“LC”) amino acid sequence

Light chain variable region CDR L1 (“L1”) amino acid sequence

Light chain variable region CDR L2 (“L2”) amino acid sequence

Light chain variable region CDR L3 (“L3”) amino acid sequence

TABLE 6 Informal Sequence Listing Seq. Antibody  Ref. SEQ ID No. No. NO.Sequence 232 3697 1 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTATTCCTGGAGCTGGATCCGCCAGACCCCAGGGAAGGGGCTGGAGTGGATTGGGGAAATCAATCATAGAGGAAGCACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATGTCAGTGGACACGTCCCAGAACCAGATCTCCCTGAGGGTGACCTCTGTGACCGCCGCGGACACGGCTGTATATTTCTGTGCGGGGACCAATTATGGAGAGGTTAATACGAGTAACCAGTACTTCTTCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 232 3698 2QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYSWSWIRQTPGKGLEWIGEINHRGSTNYNPSLKSRVTMSVDTSQNQISLRVTSVTAADTAVYFCAGTNYGEVNTSNQYFFGMDVWGQGTTVTVSS 232 3699 3 GSFSGYSWS 232 3700 4GGGTCCTTCAGTGGTTATTCCTGGAGC 232 3701 5 EINHRGSTNYNPSLKS 232 3702 6GAAATCAATCATAGAGGAAGCACCAACTACAACCCGTCCCTCAAGAG T 232 3703 7AGTNYGEVNTSNQYFFGMDV 232 3704 8GCGGGGACCAATTATGGAGAGGTTAATACGAGTAACCAGTACTTCTT CGGTATGGACGTC 232 3705 9GACATCCAGGTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTGGCACCTATTTAAATTGGTATCAGCAGAAACCAGGGAAACCCCCTAAACTCCTGATCTATGCTGCATCCAATTTGGAAAGTGGGGTCCCATCAAGTTTCAGTGGCAGTGGATCTGGGACACATTTCACTCTCACCATCAGCAGTCTGCAACCTGAACATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA 232 3706 10DIQVTQSPSSLSASVGDRVTITCRASQSIGTYLNWYQQKPGKPPKLLIYAASNLESGVPSSFSGSGSGTHFTLTISSLQPEHFATYYCQQSYSTPLTFGGGTK VEIK 232 3707 11RASQSIGTYLN 232 3708 12 CGGGCAAGTCAGAGCATTGGCACCTATTTAAAT 232 3709 13AASNLES 232 3710 14 GCTGCATCCAATTTGGAAAGT 232 3711 15 QQSYSTPLT 232 371216 CAACAGAGTTACAGTACCCCGCTCACT 233 3713 17CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTCCCTCCATCAGCAGTGGTGATTACTACTGGACTTGGATCCGCCAGCCCCCAGGGAAGGGCCTGGAGTGGATTGGCTACATCTATAACAGTGGGAGCACCGACTACAACCCGTCCCTCAAGAGTCGTATCACCATGTCACTAGACAGGTCCAAGAACCAGTTCTCCCTGAATCTGAGCTCTGTGACTGCCGCAGACACGGCCGTGTATTTCTGTGCCAGGGATGTGGGTACTCTGGTACTACCAACTGTTGCTTACTACTACGGCATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCT CCTCA 233 3714 18QVQLQESGPGLVKPSQTLSLTCTVSGPSISSGDYYWTWIRQPPGKGLEWIGYIYNSGSTDYNPSLKSRITMSLDRSKNQFSLNLSSVTAADTAVYFCARDVGTLVLPTVAYYYGMDVWGQGTTVTVSS 233 3715 19 PSISSGDYYWT 233 3716 20CCCTCCATCAGCAGTGGTGATTACTACTGGACT 233 3717 21 YIYNSGSTDYNPSLKS 233 371822 TACATCTATAACAGTGGGAGCACCGACTACAACCCGTCCCTCAAGAG T 233 3719 23ARDVGTLVLPTVAYYYGMDV 233 3720 24GCCAGGGATGTGGGTACTCTGGTACTACCAACTGTTGCTTACTACTAC GGCATGGACGTC 233 372125 GAAATTGTATTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCGGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTGAGAGTATTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGACTCCTCATCTATGATGCGTCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGTCTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCACCCCTGGTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA 233 3722 26EIVLTQSPGTLSLSPGERATLSCRASESISSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISSLEPEDFAVYYCQQYGSSPLVTFGPG TKVDIK 233 3723 27RASESISSSYLA 233 3724 28 AGGGCCAGTGAGAGTATTAGCAGCAGCTACTTAGCC 233 372529 DASSRAT 233 3726 30 GATGCGTCCAGCAGGGCCACT 233 3727 31 QQYGSSPLVT 2333728 32 CAGCAGTATGGTAGCTCACCCCTGGTCACT 234 3729 33CAGGTCCAGCTGGTGCAGTCTGGAACTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGTAAGGCTGCTGGTTACACCTTTAGCAACTACGGTGTCAGTTGGGTGCGACAGGCCCCTGGACAGGGGCTTGAGTGGATGGGATGGATCAGCGCTTATAATGGTAACACAAAATTTGCACAGAAGGTCCAGGGCAGACTCACCATGACCACAGACACATCTACCAGCACAGCCTACATGGAATTGAGGAACCTCAGATCTGACGACACGGCCGTGTATTATTGTGCGAGAGAATCAGGGGCAACAGCGGCTGCTATGTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 234 3730 34QVQLVQSGTEVKKPGASVKVSCKAAGYTFSNYGVSWVRQAPGQGLEWMGWISAYNGNTKFAQKVQGRLTMTTDTSTSTAYMELRNLRSDDTAVYYCARESGATAAAMFDYWGQGTLVTVSS 234 3731 35 YTFSNYGVS 234 3732 36TACACCTTTAGCAACTACGGTGTCAGT 234 3733 37 WISAYNGNTKFAQKVQG 234 3734 38TGGATCAGCGCTTATAATGGTAACACAAAATTTGCACAGAAGGTCCA GGGC 234 3735 39ARESGATAAAMFDY 234 3736 40 GCGAGAGAATCAGGGGCAACAGCGGCTGCTATGTTTGACTAC234 3737 41 GAAACGACACTCACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACATCTACTTGAGTTGGTTTCAACAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTCACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAATCGCCAGGGTGGAGGCTGAGGATGTTGCAGTTTATTACTGCATGCAAGCTATACACTGGCCTCGAACTTTTGGCCAGGGGACCAAAGTGGATAT CAAA 234 3738 42ETTLTQSPLSLPVTLGQPASISCRSSQSLEYSDGNIYLSWFQQRPGQSPRRLIYKVSHRDSGVPDRFSGSGSGTDFTLKIARVEAEDVAVYYCMQAIHWPR TFGQGTKVDIK 234 373943 RSSQSLEYSDGNIYLS 234 3740 44AGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACATCTACTTGAG T 234 3741 45 KVSHRDS234 3742 46 AAGGTTTCTCACCGGGACTCT 234 3743 47 MQAIHWPRT 234 3744 48ATGCAAGCTATACACTGGCCTCGAACT 235 3745 49CAGGTGCAGCTGCAGGAGTCGGGCCCAAGACTGGTGAAGCCTTCACAGACCCTGTCCCTCATCTGCGATGTCTCTGGTGGCTCCATCGGCAGTGGTGACCACTACTGGAGTTGGATCCGCCAGCCCCCCGGGAAGGGCCTCGAGTGGATTGGGTACATCTATTACAGTGGGACCACTTACTACAACCCGTCCCTCAAGAGTCGAGTGACCATTTCAGCAGACACGTCCAAGAACCAGTTGTCCCTGAAATTGAGTTCTGTGACTGCCGCAGACACGGCCATTTATTTCTGTGCCAGAGATGGGGGTTATGATCACGTCTGGGGGACTCATCGTTATTTCGACAAGTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 235 3746 50QVQLQESGPRLVKPSQTLSLICDVSGGSIGSGDHYWSWIRQPPGKGLEWIGYIYYSGTTYYNPSLKSRVTISADTSKNQLSLKLSSVTAADTAIYFCARDGGYDHVWGTHRYFDKWGQGTLVTVSS 235 3747 51 GSIGSGDHYWS 235 3748 52GGCTCCATCGGCAGTGGTGACCACTACTGGAGT 235 3749 53 YIYYSGTTYYNPSLKS 235 375054 TACATCTATTACAGTGGGACCACTTACTACAACCCGTCCCTCAAGAGT 235 3751 55ARDGGYDHVWGTHRYFDK 235 3752 56GCCAGAGATGGGGGTTATGATCACGTCTGGGGGACTCATCGTTATTTC GACAAG 235 3753 57GAAATTGTATTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCCGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAACAGTTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGTTTCCACCAGGGCCACTGGCATCCCAGACCGGTTCAGTGGCAGCGGGTCTGGGACAGACTTCACCCTCACCATCAGCAGACTGGAACCTGAAGATTTTGCAATGTATCACTGTCAGCAGTATGGTGCCTCACCTTGGACGTTCGGCCAAGGGACCAAAGTGGATATCAAA 235 3754 58EIVLTQSPGTLSLSPGERATLSCRASQSVSNSYLAWYQQKPGQAPRLLIYGVSTRATGIPDRFSGSGSGTDFTLTISRLEPEDFAMYHCQQYGASPWTFG QGTKVDIK 235 3755 59RASQSVSNSYLA 235 3756 60 AGGGCCAGTCAGAGTGTTAGCAACAGTTACTTAGCC 235 375761 GVSTRAT 235 3758 62 GGTGTTTCCACCAGGGCCACT 235 3759 63 QQYGASPWT 2353760 64 CAGCAGTATGGTGCCTCACCTTGGACG 236 3761 65GAGGTGCAGCTGTTGGAGTCTGGAGGTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAGGGCCTCTGGTTACACCTTTAGAAACTATGGCCTCACCTGGGTGCGGCAGGCCCCCGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAATGGAAACACAAACTATGCACAGAAGTTCCAGGGCAGAGTCACACTGACCACGGACACATCCACGAGCACAGCCTACATGGAACTGAGGAGCCTAAGATCTGACGACACGGCCGTGTATTTCTGTGCGAGAGACGTCCCCGGCCACGGCGCTGCCTTCATGGACGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCA 236 3762 66EVQLLESGGEVKKPGASVKVSCRASGYTFRNYGLTWVRQAPGQGLEWMGWISAYNGNTNYAQKFQGRVTLTTDTSTSTAYMELRSLRSDDTAVYFCARDVPGHGAAFMDVWGTGTTVTVSS 236 3763 67 YTFRNYGLT 236 3764 68TACACCTTTAGAAACTATGGCCTCACC 236 3765 69 WISAYNGNTNYAQKFQG 236 3766 70TGGATCAGCGCTTACAATGGAAACACAAACTATGCACAGAAGTTCCA GGGC 236 3767 71ARDVPGHGAAFMDV 236 3768 72 GCGAGAGACGTCCCCGGCCACGGCGCTGCCTTCATGGACGTC236 3769 73 GACATCCAGTTGACCCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGGCAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAAGCCAGTGATACAAATATCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGATTTCTAACCGAGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTCATTTCACACTGAGAATCAGCAGGGTGGAGGCTGACGATGTTGCGGTTTATTACTGCATGCAGGGTACACACTGGCCTCCGGCGTTCGGCCAGGGGACCAAAGTGGATATC AAA 236 3770 74DIQLTQSPLSLPVTLGQPASISCRSSQSLEASDTNIYLSWFQQRPGQSPRRLIYKISNRDSGVPDRFSGSGSGTHFTLRISRVEADDVAVYYCMQGTHWPPA FGQGTKVDIK 236 377175 RSSQSLEASDTNIYLS 236 3772 76AGGTCTAGTCAAAGCCTCGAAGCCAGTGATACAAATATCTACTTGAG T 236 3773 77 KISNRDS236 3774 78 AAGATTTCTAACCGAGACTCT 236 3775 79 MQGTHWPPA 236 3776 80ATGCAGGGTACACACTGGCCTCCGGCG 237 3777 81CAGGTCCAGCTGGTACAGTCTGGATCTGAGGTGAAGAAGCCTGGGGCCGCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACATCTTTGCCAACTTTGGTGTCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGTTCCAGGGCAGAGTCATCATGACCACAGACACATCCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTATTGTGCGAGAGACCCCCCCGCCTACGCCGCTACATTGATGGACGTCTGGGGCAAAGGGACCACGGTCACTGTCTCCTCA 237 3778 82QVQLVQSGSEVKKPGAAVKVSCKASGYIFANFGVSWVRQAPGQGLEWMGWISAYNGNTNYAQKFQGRVIMTTDTSTSTAYMELRSLRSDDTAVYYCARDPPAYAATLMDVWGKGTTVTVSS 237 3779 83 YIFANFGVS 237 3780 84TACATCTTTGCCAACTTTGGTGTCAGC 237 3781 85 WISAYNGNTNYAQKFQG 237 3782 86TGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGTTCCA GGGC 237 3783 87ARDPPAYAATLMDV 237 3784 88 GCGAGAGACCCCCCCGCCTACGCCGCTACATTGATGGACGTC237 3785 89 GAAATTGTATTGACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGTCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAACACAGTGATACAAACACCTACTTGACTTGGTATCAGCAGAGGCCAGGCCAATCTCCAAGGCGGCTACTTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGTACACACTGGCCTCCGACGTTCGGCCAAGGGACCAAAGTGGATAT CAAA 237 3786 90EIVLTQSPLSLPVTLGQSASISCRSSQSLEHSDTNTYLTWYQQRPGQSPRRLLYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGTHWP PTFGQGTKVDIK 237 378791 RSSQSLEHSDTNTYLT 237 3788 92AGGTCTAGTCAAAGCCTCGAACACAGTGATACAAACACCTACTTGAC T 237 3789 93 KVSNRDS237 3790 94 AAGGTTTCTAACCGGGACTCT 237 3791 95 MQGTHWPPT 237 3792 96ATGCAAGGTACACACTGGCCTCCGACG 238 3793 97CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAGGGTCTCCTGCAAGGCCTCTGGAGGCACCTTCAGGGGCTATGGTCTCAGCTGGGTGCGACAGGCCCCTGGACAGGGACTCGAGTGGATGGGAGGGATCACCCATCTTTTTGGGACAGTCAGCTACGCTCCGAAGTTCCAGGGCAGACTCACGATCACCGCGGACGCATCCACGGGCACAGCCTACATGGAGCTGAGCAGCCTGATATCTGAGGACACGGCCGTATATTTTTGTGCGAGAGATGCTTACGAAGTGTGGACCGGCTCTTATCTCCCCCCTTTTGACTACTGGGGCCAGGGAACAATGGTCACCGTCTCTTCA 238 3794 98QVQLVQSGAEVKKPGSSVRVSCKASGGTFRGYGLSWVRQAPGQGLEWMGGITHLFGTVSYAPKFQGRLTITADASTGTAYMELSSLISEDTAVYFCARDAYEVWTGSYLPPFDYWGQGTMVTVSS 238 3795 99 GTFRGYGLS 238 3796 100GGCACCTTCAGGGGCTATGGTCTCAGC 238 3797 101 GITHLFGTVSYAPKFQG 238 3798 102GGGATCACCCATCTTTTTGGGACAGTCAGCTACGCTCCGAAGTTCCAG GGC 238 3799 103ARDAYEVWTGSYLPPFDY 238 3800 104GCGAGAGATGCTTACGAAGTGTGGACCGGCTCTTATCTCCCCCCTTTT GACTAC 238 3801 105GATATTGTGATGACTCAGTCTCCAGGCACCCTGTCTTTGTCTCCCGGGGAAAGAGTCACCCTCTCCTGCAGGGCCAGTCAGATTATTCCAAGCAGTTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATTCACCAGGGCCACTGACATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTATATTATTGTCAGCAGTATGGTAGTTCATTTCTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA 238 3802 106DIVMTQSPGTLSLSPGERVTLSCRASQIIPSSYLAWYQQKPGQAPRLLIYGAFTRATDIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSFLTFGGG TKVEIK 238 3803 107RASQIIPSSYLA 238 3804 108 AGGGCCAGTCAGATTATTCCAAGCAGTTACTTAGCC 238 3805109 GAFTRAT 238 3806 110 GGTGCATTCACCAGGGCCACT 238 3807 111 QQYGSSFLT238 3808 112 CAGCAGTATGGTAGTTCATTTCTCACT 239 3809 113CAGGTCCAGCTTGTGCAGTCTGGGCCTGAGGTAAAGAAGCCTGGGTCCTCAGTGACGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAACTATGGTATTGCTTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATCAACAATCCCTATCCTTGGAACAGCAAGCTACAGACAGAGCTTAAAGGACAGAGTCACAATTACCGCGGACGCTTCCACGACCACAGTCTACATGGAAATGACTCGCCTCAGAACTGAGGACACGGCCGTCTATTTTTGTGCGAGAGTTCCGGAGAGTCTTGTGGCATCAAACGCTTATGCTGTTTGGGGCCAAGGGACGGTGGTCACTGTCTCCTCA 239 3810 114QVQLVQSGPEVKKPGSSVTVSCKASGGTFSNYGIAWVRQAPGQGLEWMGSTIPILGTASYRQSLKDRVTITADASTTTVYMEMTRLRTEDTAVYFCARVPESLVASNAYAVWGQGTVVTVSS 239 3811 115 GTFSNYGIA 239 3812 116GGCACCTTCAGCAACTATGGTATTGCT 239 3813 117 STIPILGTASYRQSLKD 239 3814 118TCAACAATCCCTATCCTTGGAACAGCAAGCTACAGACAGAGCTTAAA GGAC 239 3815 119ARVPESLVASNAYAV 239 3816 120GCGAGAGTTCCGGAGAGTCTTGTGGCATCAAACGCTTATGCTGTT 239 3817 121GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGCCAGGACATTAGCACCTGGTTAGCCTGGTATCAGCAGAGACCAGGGAAAGCCCCAAAACTCCTGATCTACACTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTACCAGTTTCCCATTCACTTTCGGCCCTGGGACCAAGCTGGAGATCAAA 239 3818 122DIQMTQSPSSVSASVGDRVTITCRASQDISTWLAWYQQRPGKAPKLLIYTASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQGTSFPFTFGPGT KLEIK 239 3819 123RASQDISTWLA 239 3820 124 CGGGCGAGCCAGGACATTAGCACCTGGTTAGCC 239 3821 125TASSLQS 239 3822 126 ACTGCATCCAGTTTGCAAAGT 239 3823 127 QQGTSFPFT 2393824 128 CAACAGGGTACCAGTTTCCCATTCACT 240 3825 129GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGATGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCTTCTGGATACACCTTCACTAACTATGCTATACATTGGGTGCGCCAGGCCCCCGGCCAAAGCCTTGAGTGGATGGGATGGATCAACGCTGGCAATGGTAACACACAATATTCACAGAAGTTCCAGGGCAGAGTCACCTTTACCAGGGACACATCCGCGAGCACGGTCTACATGGACCTGAGCAGCCTGAGATCTGAAGACACGGCTGTCTATTACTGTGCGAGAGGCCAAATTGTTGTTATACCACGTGCTAATTTCTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 240 3826 130EVQLVESGAEMKKPGASVKVSCKASGYTFTNYAIHWVRQAPGQSLEWMGWINAGNGNTQYSQKFQGRVTFTRDTSASTVYMDLSSLRSEDTAVYYCARGQIVVIPRANFWFDPWGQGTLVTVSS 240 3827 131 YTFTNYAIH 240 3828 132TACACCTTCACTAACTATGCTATACAT 240 3829 133 WINAGNGNTQYSQKFQG 240 3830 134TGGATCAACGCTGGCAATGGTAACACACAATATTCACAGAAGTTCCA GGGC 240 3831 135ARGQIVVIPRANFWFDP 240 3832 136GCGAGAGGCCAAATTGTTGTTATACCACGTGCTAATTTCTGGTTCGAC CCC 240 3833 137GATATTGTGCTGACCCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTCATGGATACAACTATTTGGATTGGTACTTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAACTCTACAAACTCCGATCACCTTCGGCCAAGGGACACGAATGGAGAT TAAA 240 3834 138DIVLTQSPLSLPVTPGEPASISCRSSQSLLHSHGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQTLQTPI TFGQGTRMEIK 240 3835139 RSSQSLLHSHGYNYLD 240 3836 140AGGTCTAGTCAGAGCCTCCTGCATAGTCATGGATACAACTATTTGGAT 240 3837 141 LGSNRAS240 3838 142 TTGGGTTCTAATCGGGCCTCC 240 3839 143 MQTLQTPIT 240 3840 144ATGCAAACTCTACAAACTCCGATCACC 241 3841 145GAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTTACAGACCCTGTCCGTCACCTGCAGTGTCTCTGGTGGCTCCATCAGCAGTGGTGATAACTACTGGAGCTGGATCCGCCAGCGCCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATTACAGTGGGACCACCTACTACAATCCGTCCCTCAAGAGTCGAGTTACCATATCAGCAGACAGGTCTAAGAATCAGTTTTCTCTGAAGATGAATTCTCTGAGTGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGATGGCGGATATGATCACATCTGGGGGACTCATCGTTATTTCGCCCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 241 3842 146EVQLQESGPGLVKPLQTLSVTCSVSGGSISSGDNYWSWIRQRPGKGLEWIGYIYYSGTTYYNPSLKSRVTISADRSKNQFSLKMNSLSAADTAVYYCARDGGYDHIWGTHRYFALWGQGTLVTVSS 241 3843 147 GSISSGDNYWS 241 3844 148GGCTCCATCAGCAGTGGTGATAACTACTGGAGC 241 3845 149 YIYYSGTTYYNPSLKS 241 3846150 TACATCTATTACAGTGGGACCACCTACTACAATCCGTCCCTCAAGAGT 241 3847 151ARDGGYDHIWGTHRYFAL 241 3848 152GCGAGAGATGGCGGATATGATCACATCTGGGGGACTCATCGTTATTT CGCCCTC 241 3849 153GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACAGCGACTACTTGGCCTGGTACCAGCAGAAACTTGGCCAGGCTCCCAGGCTCCTCATTTATGGTGTATCCAACAGGGCCACTGGCATCCCAGACAGGTTTACTGGGAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTCTATCACTGTCAGCAGTATGGTACCTCACCGTGGACGTTCGGCCAAGGGACCAAGGTGGAGATCAAA 241 3850 154ETTLTQSPGTLSLSPGERATLSCRASQSVNSDYLAWYQQKLGQAPRLLIYGVSNRATGIPDRFTGSGSGTDFTLTISRLEPEDFAVYHCQQYGTSPWTFG QGTKVEIK 241 3851 155RASQSVNSDYLA 241 3852 156 AGGGCCAGTCAGAGTGTTAACAGCGACTACTTGGCC 241 3853157 GVSNRAT 241 3854 158 GGTGTATCCAACAGGGCCACT 241 3855 159 QQYGTSPWT241 3856 160 CAGCAGTATGGTACCTCACCGTGGACG 242 3857 161CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGAGGCCTGGGTCCTCGGTGAAAGTCTCCTGTAAGGCCTCTGGAGGCACCTTCAGTAGTTATGCTCTCTCCTGGGTACGGCAGGCCCCTGGACAAGGACTTGAGTGGATAGGGGGGATCATCCCTATGCATCGTGTAACAAATTACGCACAGAAATTTCGGGGCAGAGTCACAATTTCCGCGGACACATCCACGAGTACGGCCTACTTGGAGGTGAACAGCCTGAGAGTTGAGGACACGGCCATGTATTACTGTGCGAGAGTGTTTTTCGGAACTTGTGGCGGTGCTTCGTGCTTCCCCTCTGACCTCTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA 242 3858 162QVQLVQSGAEVKRPGSSVKVSCKASGGTFSSYALSWVRQAPGQGLEWIGGIIPMHRVTNYAQKFRGRVTISADTSTSTAYLEVNSLRVEDTAMYYCARVFFGTCGGASCFPSDLWGQGTLVTVSS 242 3859 163 GTFSSYALS 242 3860 164GGCACCTTCAGTAGTTATGCTCTCTCC 242 3861 165 GIIPMHRVTNYAQKFRG 242 3862 166GGGATCATCCCTATGCATCGTGTAACAAATTACGCACAGAAATTTCG GGGC 242 3863 167ARVFFGTCGGASCFPSDL 242 3864 168GCGAGAGTGTTTTTCGGAACTTGTGGCGGTGCTTCGTGCTTCCCCTCT GACCTC 242 3865 169GAAATTGTGTTGACACAGTCTCCATCCTTCGTGTCTGCTTCTGTCGGAGACGGGGTCACCATCACTTGCCGGGCCAGTCAGGCCATTAGCAGTTATTTAGCCTGGTATCAGCAAAAACCAGGGCAAGCCCCTAAACTCCTGATCTATGCTGCATCCACTTTGCAAGGTGGTGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACACATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAGCAACTTCATAGTGATTTTCAGACTTTCGGCCCTGGGACCAAGGTGGAAATCAAA 242 3866 170EIVLTQSPSFVSASVGDGVTITCRASQAISSYLAWYQQKPGQAPKLLIYAASTLQGGVPSRFSGSGSGTHFTLTISSLQPEDFATYYCQQLHSDFQTFGPGT KVEIK 242 3867 171RASQAISSYLA 242 3868 172 CGGGCCAGTCAGGCCATTAGCAGTTATTTAGCC 242 3869 173AASTLQG 242 3870 174 GCTGCATCCACTTTGCAAGGT 242 3871 175 QQLHSDFQT 2423872 176 CAGCAACTTCATAGTGATTTTCAGACT 243 3873 177CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGTAGCGTCTGGATTCAGCTTCAGTATGCATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGACAGCTATATGGTATGATGGAAGTAATAAATATTATGCAGACTCCGTGAAGGGCCGATTCACGATCTCCAGAGACAATTCTAGGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCATGCCTCAACTCCATACTACATGGACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCA 243 3874 178QVQLVESGGGVVQPGRSLRLSCVASGFSFSMHGMHWVRQAPGKGLEWVTAIWYDGSNKYYADSVKGRFTISRDNSRNTLYLQMNSLRAEDTAVYYCARDHASTPYYMDVWGKGTTVTVSS 243 3875 179 FSFSMHGMH 243 3876 180TTCAGCTTCAGTATGCATGGCATGCAC 243 3877 181 AIWYDGSNKYYADSVKG 243 3878 182GCTATATGGTATGATGGAAGTAATAAATATTATGCAGACTCCGTGAA GGGC 243 3879 183ARDHASTPYYMDV 243 3880 184 GCGAGAGATCATGCCTCAACTCCATACTACATGGACGTC 2433881 185 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGCGCCACCCTCTCCTGCAGGACCAGTCAGAGGATTAGCAGCACCTACTTAGCCTGGTACCGGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATGTATGGTGCATCCAGCAGGGCCACTGGCATCCCGGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGTCTGGAGCCTGAAGATTTTGCACTATATTACTGTCAGCAGTATGGTAGCTTTCCGTGGACGTTCGGCCAAGGGACCAAGCTGGAGATCAAA 243 3882 186ETTLTQSPGTLSLSPGESATLSCRTSQRISSTYLAWYRQKPGQAPRLLMYGASSRATGIPDRFSGSGSGTDFTLTISSLEPEDFALYYCQQYGSFPWTFGQ GTKLEIK 243 3883 187RTSQRISSTYLA 243 3884 188 AGGACCAGTCAGAGGATTAGCAGCACCTACTTAGCC 243 3885189 GASSRAT 243 3886 190 GGTGCATCCAGCAGGGCCACT 243 3887 191 QQYGSFPWT243 3888 192 CAGCAGTATGGTAGCTTTCCGTGGACG 244 3889 193CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTGGAAGCCTTCGCAGACCCTGTCCCTCACCTGCGCTGTCCATGGTGGATCCCTCAGTGGCTACTCTTGGAGTTGGATCCGCCAGTCCCCAGGGAGGGGACTGGAGTGGATCGGCGAAGTCAATCGTAGGGGAACCACCAACTACAACCCCTCCCTCAAGGGTCGAGTCTCCATATCCTGGGACACGTCCAAGAACCAGGTCTCCCTGTCCCTGAGGTCTGTGACCGCCGCGGACACGGCTACATATTACTGTGCGGGGACCAATGTTGGATTCGTTAATACCCATAACGACTACTACTTCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 244 3890 194QVQLQQWGAGLWKPSQTLSLTCAVHGGSLSGYSWSWIRQSPGRGLEWIGEVNRRGTTNYNPSLKGRVSISWDTSKNQVSLSLRSVTAADTATYYCAGTNVGFVNTHNDYYFGMDVWGQGTTVTVSS 244 3891 195 GSLSGYSWS 244 3892 196GGATCCCTCAGTGGCTACTCTTGGAGT 244 3893 197 EVNRRGTTNYNPSLKG 244 3894 198GAAGTCAATCGTAGGGGAACCACCAACTACAACCCCTCCCTCAAGGG T 244 3895 199AGTNVGFVNTHNDYYFGMDV 244 3896 200GCGGGGACCAATGTTGGATTCGTTAATACCCATAACGACTACTACTTC GGTATGGACGTC 244 3897201 GATATTGTGATGACTCAGTCTCCATCCTCCCTGTCTGCATCGGTTGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATAAGCAATTATGTAAATTGGTATCAGAAAAAAACAGGTCAAGTCCCTAAACTCCTGATCTATGGTGCATCCAATTTGGAAAGTGGGGTCCCATCAAGGTTCAGTGGCGGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTATTACTGTCAACAGAGTTACAGTGTCCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA 244 3898 202DIVMTQSPSSLSASVGDRVTITCRASQSISNYVNWYQKKTGQVPKLLIYGASNLESGVPSRFSGGGSGTDFTLTISSLQPEDFATYYCQQSYSVPLTFGGG TKVEIK 244 3899 203RASQSISNYVN 244 3900 204 CGGGCAAGTCAGAGCATAAGCAATTATGTAAAT 244 3901 205GASNLES 244 3902 206 GGTGCATCCAATTTGGAAAGT 244 3903 207 QQSYSVPLT 2443904 208 CAACAGAGTTACAGTGTCCCGCTCACT 245 3905 209CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGAGGCCTGGATCCTCGGTGAAGGTCTCCTGCAAGGCGTCTGGAGGCACCTTCCGCGGCTACCATATCAGCTGGCTGCGCCAGGCCCCTGGACAGGGCCTCGAGTGGCTGGGAGGGATCACCCATTTGTTTGGGACAGTTAGTTACGCTCCGAAGTTCCAGGGCAGAGTCACCATCACCGCGGACGCATCCACGGGCACACTTTACATGGTGTTGAACAGCCTGAAACCTGAGGACACGGCCATTTATTATTGTGCGAGAGATGCTTACGAGGTGTGGACTGGTTCTTATCTCCCCCCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 245 3906 210QVQLVQSGAEVKRPGSSVKVSCKASGGTFRGYHISWLRQAPGQGLEWLGGITHLFGTVSYAPKFQGRVTITADASTGTLYMVLNSLKPEDTAIYYCARDAYEVWTGSYLPPFDYWGQGTLVTVSS 245 3907 211 GTFRGYHIS 245 3908 212GGCACCTTCCGCGGCTACCATATCAGC 245 3909 213 GITHLFGTVSYAPKFQG 245 3910 214GGGATCACCCATTTGTTTGGGACAGTTAGTTACGCTCCGAAGTTCCAG GGC 245 3911 215ARDAYEVWTGSYLPPFDY 245 3912 216GCGAGAGATGCTTACGAGGTGTGGACTGGTTCTTATCTCCCCCCTTTT GACTAC 245 3913 217GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCCGGGGAAAGAGCCACCCTCTCTTGCAGGGCCAGTCAGACTGTTACAAGCAACTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCACTCACCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCACTTTATTATTGTCAGCAGTATGGTAGTTCATTCCTCACTTTCGGCGGAGGGACCAAAGTGGATATCAAA 245 3914 218ETTLTQSPGTLSLSPGERATLSCRASQTVTSNYLAWYQQKPGQAPRLLIYDALTRATGIPDRFSGSGSGTDFTLTISRLEPEDFALYYCQQYGSSFLTFGG GTKVDIK 245 3915 219RASQTVTSNYLA 245 3916 220 AGGGCCAGTCAGACTGTTACAAGCAACTACTTAGCC 245 3917221 DALTRAT 245 3918 222 GATGCACTCACCAGGGCCACT 245 3919 223 QQYGSSFLT245 3920 224 CAGCAGTATGGTAGTTCATTCCTCACT 246 3921 225CAGGTGCAGCTGCAGGAGTCCGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCGCCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAGGGCCTCGAGTGGCTGGGAGGGATCACCCATTTGTTTGGGACAGTTAGTTACGCTCCGAAGTTCCAGGGCAGAGTCACCATCACCGCGGACGCATCCACGGGCACACTTTACATGGTGTTGAACAGCCTGAAACCTGAGGACACGGCCATTTATTATTGTGCGAGAGATGCTTACGAGGTGTGGACTGGTTCTTATCTCCCCCCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 246 3922 226QVQLQESGAEVKKPGSSVKVSCKASGGAFSSYAISWVRQAPGQGLEWLGGITHLFGTVSYAPKFQGRVTITADASTGTLYMVLNSLKPEDTAIYYCARDAYEVWTGSYLPPFDYWGQGTLVTVSS 246 3923 227 GAFSSYAIS 246 3924 228GGCGCCTTCAGCAGCTATGCTATCAGC 246 3925 229 GITHLFGTVSYAPKFQG 246 3926 230GGGATCACCCATTTGTTTGGGACAGTTAGTTACGCTCCGAAGTTCCAG GGC 246 3927 231ARDAYEVWTGSYLPPFDY 246 3928 232GCGAGAGATGCTTACGAGGTGTGGACTGGTTCTTATCTCCCCCCTTTT GACTAC 246 3929 233GAAATTGTATTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCCGGGGAAAGAGCCACCCTCTCTTGCAGGGCCAGTCAGACTGTTACAAGCAACTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCACTCACCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCACTTTATTATTGTCAGCAGTATGGTAGTTCATTCCTCACTTTCGGCGGAGGGACCAAGCTGGAGATCAAA 246 3930 234EIVLTQSPGTLSLSPGERATLSCRASQTVTSNYLAWYQQKPGQAPRLLIYDALTRATGIPDRFSGSGSGTDFTLTISRLEPEDFALYYCQQYGSSFLTFGG GTKLEIK 246 3931 235RASQTVTSNYLA 246 3932 236 AGGGCCAGTCAGACTGTTACAAGCAACTACTTAGCC 246 3933237 DALTRAT 246 3934 238 GATGCACTCACCAGGGCCACT 246 3935 239 QQYGSSFLT246 3936 240 CAGCAGTATGGTAGTTCATTCCTCACT 247 3937 241CAGGTCCAGCTGGTACAGTCTGGAGCTGAGGTGAAGGAGCCTGGGGCCTCAGTGAGGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAGCTATGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGTTCCAGGGCAGAGTCACCGTGACCACAGACACATCCACGAGCGCAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCATTTATTACTGTGCGAGAGATTCATTTTCACTGACTGGTGCTGGATTTCCTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 247 3938 242QVQLVQSGAEVKEPGASVRVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKFQGRVTVTTDTSTSAAYMELRSLRSDDTAIYYCARDSFSLTGAGFPDYWGQGTLVTVSS 247 3939 243 YTFTSYGIS 247 3940 244TACACCTTTACCAGCTATGGTATCAGC 247 3941 245 WISAYNGNTNYAQKFQG 247 3942 246TGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGTTCCA GGGC 247 3943 247ARDSFSLTGAGFPDY 247 3944 248GCGAGAGATTCATTTTCACTGACTGGTGCTGGATTTCCTGACTAC 247 3945 249GAAATTGTAATGACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTATACAGTGATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGACACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGCTACACAGTGGCCTCGCACGTTCGGCCAAGGGACCAAGGTGGAAAT CAAA 247 3946 250EIVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSDTDFTLKISRVEAEDVGVYYCMQATQWP RTFGQGTKVEIK 247 3947251 RSSQSLVYSDGNTYLN 247 3948 252AGGTCTAGTCAAAGCCTCGTATACAGTGATGGAAACACCTACTTGAA T 247 3949 253 KVSNRDS247 3950 254 AAGGTTTCTAACCGGGACTCT 247 3951 255 MQATQWPRT 247 3952 256ATGCAAGCTACACAGTGGCCTCGCACG 248 3953 257GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTCACCTTCAGTAGCTATAACATCAACTGGGTCCGCCAGGCTCCAGGGAAGGGACTGGAGTGGGTCTCATCCATTAGTGGTGGTAGTAATTACATAGACTACGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATTTGCAAATGAACAACCTGCGAGCCGAAGACACGGCTGTGTATTACTGTGCGAGACTTGGCTATGGTGGTAACCCGGAGCTTGACTATTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA 248 3954 258EVQLLESGGGLVKPGGSLRLSCVASGFTFSSYNINWVRQAPGKGLEWVSSISGGSNYIDYADSVKGRFTISRDNAKNSLYLQMNNLRAEDTAVYYCAR LGYGGNPELDYWGQGTLVTVSS248 3955 259 FTFSSYNIN 248 3956 260 TTCACCTTCAGTAGCTATAACATCAAC 248 3957261 SISGGSNYIDYADSVKG 248 3958 262TCCATTAGTGGTGGTAGTAATTACATAGACTACGCAGACTCAGTGAA GGGC 248 3959 263ARLGYGGNPELDY 248 3960 264 GCGAGACTTGGCTATGGTGGTAACCCGGAGCTTGACTAT 2483961 265 CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGACAGAGGGTCACCATCTCCTGCACCGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTACCAGCAACGTCCAGGAACAGCCCCCAAACTCCTCATCTATGCTAATAACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACCTCAGTCTGAGTAGTTCGAGGGTATTCGGCGGAGGGACCAAGCTGACCGT CCTC 248 3962 266QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQRPGTAPKLLIYANNNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDLSLSSS RVFGGGTKLTVL 248 3963267 TGSSSNIGAGYDVH 248 3964 268ACCGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 248 3965 269 ANNNRPS 248 3966270 GCTAATAACAATCGGCCCTCA 248 3967 271 QSYDLSLSSSRV 248 3968 272CAGTCCTATGACCTCAGTCTGAGTAGTTCGAGGGTA 249 3969 273CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAAACACTCATGTGCAGCCTCTGGATTCACCTTCAATAACTATGCTATACACTGGGTCCGCCAGGCTCCAGGCAAGGGCCTGGAGTGGGTGGCAGCTATCTCATATGATGGAAGCAATGAATACTACTCAAACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGTACACGCTGTATCTGCAAATGAACAGCCTGAGACCTGAGGACACGGCTGTGTATTACTGTGCGAGAGGCGCCTCCTATTACTATGTGAGTAGTGACCTTGGCTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 249 3970 274QVQLVQSGGGVVQPGRSLKHSCAASGFTFNNYAIHWVRQAPGKGLEWVAAISYDGSNEYYSNSVKGRFTISRDNSKYTLYLQMNSLRPEDTAVYYCARGASYYYVSSDLGYWGQGTLVTVSS 249 3971 275 FTFNNYAIH 249 3972 276TTCACCTTCAATAACTATGCTATACAC 249 3973 277 AISYDGSNEYYSNSVKG 249 3974 278GCTATCTCATATGATGGAAGCAATGAATACTACTCAAACTCCGTGAA GGGC 249 3975 279ARGASYYYVSSDLGY 249 3976 280GCGAGAGGCGCCTCCTATTACTATGTGAGTAGTGACCTTGGCTAC 249 3977 281CAGCCTGTGCTGACTCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGTCAGGTTATGATGTGCACTGGTATCAGCAGCTTCCAGGAACAGCCCCCAAAGTCGTCATCTATGGTAACATCAATCGGCCCTCAGGGGTCCCTGAGCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCCTGAGTGCCTCTTGGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 249 3978 282QPVLTQPPSVSGAPGQRVTISCTGSSSNIGSGYDVHWYQQLPGTAPKVVIYGNINRPSGVPERFSGSKSGTSASLAITGLQAEDEADYYCQSYDSLSASW VFGGGTKLTVL 249 3979283 TGSSSNIGSGYDVH 249 3980 284ACTGGGAGCAGCTCCAACATCGGGTCAGGTTATGATGTGCAC 249 3981 285 GNINRPS 249 3982286 GGTAACATCAATCGGCCCTCA 249 3983 287 QSYDSLSASWV 249 3984 288CAGTCCTATGACAGCCTGAGTGCCTCTTGGGTG 250 3985 289CAGGTCCAGCTTGTGCAGTCTGGACCAGAGGTGAAAAAGACCAGAGAGTCTCTGAAGATCTACTGTAAGGGTTCTGGATACAGCTTTATCAGCCACTGGATCGGCTGGGTGCGCCAGAAACCCGGGAAAGGCCTGGAGTGGATGGGGATCATCTATCCGGGTGACTCTGACACCAGATACAGCCCGTCCTTCCAAGGCCAGGTCGCCATCTCAGCCGACAAGTCCATCAACACCGCCTACCTGCAGTGGAGCAGCCTGAAGTCCTCGGACACCGCCATATATTACTGTGCGAGTGTAATGCTTCGGGGGATTATGTGGGGCCAGGGAACCC TGGTCACCGTCTCCTCA 2503986 290 QVQLVQSGPEVKKTRESLKIYCKGSGYSFISHWIGWVRQKPGKGLEWMGIIYPGDSDTRYSPSFQGQVAISADKSINTAYLQWSSLKSSDTAIYYCASV MLRGIMWGQGTLVTVSS250 3987 291 YSFISHWIG 250 3988 292 TACAGCTTTATCAGCCACTGGATCGGC 250 3989293 IIYPGDSDTRYSPSFQG 250 3990 294ATCATCTATCCGGGTGACTCTGACACCAGATACAGCCCGTCCTTCCAA GGC 250 3991 295ASVMLRGIM 250 3992 296 GCGAGTGTAATGCTTCGGGGGATTATG 250 3993 297GACATCCGGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCAAGTATCTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTACGATGCATCCAATTTGGAAACAGGGGTCCCATCAAGATTCAGTGGAAGTGGATCTGGGACAGATTTTACTTTCACCATCAGCAGCCTGCAGCCTGAAGATATTGCAACATATTACTGTCAGCCGTATGATAATCTCCCTCCGCCGCTCACTTTCGGCGGAGGGACCAAGCTGGAGATCAAA 250 3994 298DIRLTQSPSSLSASVGDRVTITCQASQDISKYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQPYDNLPPPLTFGG GTKLEIK 250 3995299 QASQDISKYLN 250 3996 300 CAGGCGAGTCAGGACATTAGCAAGTATCTAAAT 250 3997301 DASNLET 250 3998 302 GATGCATCCAATTTGGAAACA 250 3999 303 QPYDNLPPPLT250 4000 304 CAGCCGTATGATAATCTCCCTCCGCCGCTCACT 251 4001 305GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGTCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTGACAATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGGTATATTTTATGATGGAAGTAATAAACAATATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAGCACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGCCCCTTACGATATTTGGAGTGGTTATTGTCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 251 4002 306EVQLLESGGGVVQSGRSLRLSCAASGFTFSDNGMHWVRQAPGKGLEWVAGIFYDGSNKQYADSVKGRFTISRDNSKSTLYLQMNSLRAEDTAVYYCARAPYDIWSGYCLDYWGQGTLVTVSS 251 4003 307 FTFSDNGMH 251 4004 308TTCACCTTCAGTGACAATGGCATGCAC 251 4005 309 GIFYDGSNKQYADSVKG 251 4006 310GGTATATTTTATGATGGAAGTAATAAACAATATGCAGACTCCGTGAA GGGC 251 4007 311ARAPYDIWSGYCLDY 251 4008 312GCGAGAGCCCCTTACGATATTTGGAGTGGTTATTGTCTTGACTAC 251 4009 313GACATCCAGATGACTCAGACTCCAGCCACCCTGTCTATGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACAACAACTTAGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCTACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGAGACAGAGTTCACTCTCACTATCAGCAGCCTGCAGTCTGAAGATTTTGCGGTTTATCACTGTCAGCAGTATAGTATCTGGCCTCAGACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 251 4010 314DIQMTQTPATLSMSPGERATLSCRASQSVNNNLAWYQQRPGQAPRLLIYGASTRATGIPARFSGSGSETEFTLTISSLQSEDFAVYHCQQYSIWPQTFGQ GTKLEIK 251 4011 315RASQSVNNNLA 251 4012 316 AGGGCCAGTCAGAGTGTTAACAACAACTTAGCC 251 4013 317GASTRAT 251 4014 318 GGTGCATCTACCAGGGCCACT 251 4015 319 QQYSIWPQT 2514016 320 CAGCAGTATAGTATCTGGCCTCAGACT 252 4017 321GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACTATTGGAACGTACTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAAACCAGATGGAAGTGAGCAATATTATGGGGACTCGGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAATTCCCTGTATCTGCAAATGCACAGCCTGAGAGCCGAGGACGCGGCTGTCTTTTACTGTGCGAGGGATACTCCCGACGTATTACGACATTTGGAGTGGCCCCCTGTAGGTGCTTTTGATATCTGGGGCCAAGGGACCACGGTCACCGTC TCCTCA 252 4018 322EVQLVESGGGLVQPGGSLRLSCAASGFTIGTYWMSWVRQAPGKGLEWVANIKPDGSEQYYGDSVKGRFTISRDNAKNSLYLQMHSLRAEDAAVFYCARDTPDVLRHLEWPPVGAFDIWGQGTTVTVSS 252 4019 323 FTIGTYWMS 252 4020 324TTCACTATTGGAACGTACTGGATGAGC 252 4021 325 NIKPDGSEQYYGDSVKG 252 4022 326AACATAAAACCAGATGGAAGTGAGCAATATTATGGGGACTCGGTGAA GGGC 252 4023 327ARDTPDVLRHLEWPPVGAFDI 252 4024 328GCGAGGGATACTCCCGACGTATTACGACATTTGGAGTGGCCCCCTGT AGGTGCTTTTGATATC 2524025 329 GAAATTGTAATGACGCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTCTTTTCTACAGCTCCACCAATCAGCACTACTTGGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTGAGCTGCTCATTTACTGGGCATCTATCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCCGCAGATGTGGCAGTTTATTACTGTCAGCAGTATTATAGTAGTCCTCAAACTTTTGGCCAGGGGACCAAGGTGGAA ATCAAA 252 4026 330EIVMTQSPDSLAVSLGERATINCKSSQSLFYSSTNQHYLAWYQQKPGQPPELLIYWASIRESGVPDRFSGSGSGTDFTLTISSLQAADVAVYYCQQYYSSP QTFGQGTKVEIK 2524027 331 KSSQSLFYSSTNQHYLA 252 4028 332AAGTCCAGCCAGAGTCTTTTCTACAGCTCCACCAATCAGCACTACTTG GCT 252 4029 333WASIRES 252 4030 334 TGGGCATCTATCCGGGAATCC 252 4031 335 QQYYSSPQT 2524032 336 CAGCAGTATTATAGTAGTCCTCAAACT 253 4033 337CAGGTCCAGCTTGTGCAGTCTGGAACTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGTAAGGCTGCTGGTTACACCTTTAGCAACTACGGTGTCAGTTGGGTGCGACAGGCCCCTGGACAGGGGCTTGAGTGGATGGGATGGATCAGCGCTTATAATGGTAACACAAAATTTGCACAGAAGGTCCAGGGCAGACTCACCATGACCACAGACACATCTACCAGCACAGCCTACATGGAATTGAGGAACCTCAGATCTGACGACACGGCCGTGTATTATTGTGCGAGAGAATCAGGGGCAACAGCGGCTGCTATGTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 253 4034 338QVQLVQSGTEVKKPGASVKVSCKAAGYTFSNYGVSWVRQAPGQGLEWMGWISAYNGNTKFAQKVQGRLTMTTDTSTSTAYMELRNLRSDDTAVYYCARESGATAAAMFDYWGQGTLVTVSS 253 4035 339 YTFSNYGVS 253 4036 340TACACCTTTAGCAACTACGGTGTCAGT 253 4037 341 WISAYNGNTKFAQKVQG 253 4038 342TGGATCAGCGCTTATAATGGTAACACAAAATTTGCACAGAAGGTCCA GGGC 253 4039 343ARESGATAAAMFDY 253 4040 344 GCGAGAGAATCAGGGGCAACAGCGGCTGCTATGTTTGACTAC253 4041 345 GAAATTGTATTGACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACATCTACTTGAGTTGGTTTCAACAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTCACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAATCGCCAGGGTGGAGGCTGAGGATGTTGCAGTTTATTACTGCATGCAAGCTATACACTGGCCTCGAACTTTTGGCCAGGGGACCAAGGTGGAGAT CAAA 253 4042 346EIVLTQSPLSLPVTLGQPASISCRSSQSLEYSDGNIYLSWFQQRPGQSPRRLIYKVSHRDSGVPDRFSGSGSGTDFTLKIARVEAEDVAVYYCMQAIHWPR TFGQGTKVEIK 253 4043347 RSSQSLEYSDGNIYLS 253 4044 348AGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACATCTACTTGAG T 253 4045 349 KVSHRDS253 4046 350 AAGGTTTCTCACCGGGACTCT 253 4047 351 MQAIHWPRT 253 4048 352ATGCAAGCTATACACTGGCCTCGAACT 254 4049 353GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGTCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTGACAATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGGTATATTTTATGATGGAAGTAATAAACAATATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAGCACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGCCCCTTACGATATTTGGAGTGGTTATTGTCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 254 4050 354EVQLVESGGGVVQSGRSLRLSCAASGFTFSDNGMHWVRQAPGKGLEWVAGIFYDGSNKQYADSVKGRFTISRDNSKSTLYLQMNSLRAEDTAVYYCARAPYDIWSGYCLDYWGQGTLVTVSS 254 4051 355 FTFSDNGMH 254 4052 356TTCACCTTCAGTGACAATGGCATGCAC 254 4053 357 GIFYDGSNKQYADSVKG 254 4054 358GGTATATTTTATGATGGAAGTAATAAACAATATGCAGACTCCGTGAA GGGC 254 4055 359ARAPYDIWSGYCLDY 254 4056 360GCGAGAGCCCCTTACGATATTTGGAGTGGTTATTGTCTTGACTAC 254 4057 361GACATCCGGTTGACCCAGTCTCCAGCCACCCTGTCTATGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACAACAACTTAGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCTACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGAGACAGAGTTCACTCTCACTATCAGCAGCCTGCAGTCTGAAGATTTTGCGGTTTATCACTGTCAGCAGTATAGTATCTGGCCTCAGACTTTTGGCCAGGGGACCAAAGTGGATATCAAA 254 4058 362DIRLTQSPATLSMSPGERATLSCRASQSVNNNLAWYQQRPGQAPRLLIYGASTRATGIPARFSGSGSETEFTLTISSLQSEDFAVYHCQQYSIWPQTFGQG TKVDIK 254 4059 363RASQSVNNNLA 254 4060 364 AGGGCCAGTCAGAGTGTTAACAACAACTTAGCC 254 4061 365GASTRAT 254 4062 366 GGTGCATCTACCAGGGCCACT 254 4063 367 QQYSIWPQT 2544064 368 CAGCAGTATAGTATCTGGCCTCAGACT 255 4065 369GAGGTGCAGCTGTTGGAGTCTGGGGGAGCCTTGGTCGAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTTAACACGTATTCCATGAACTGGGTCCGCCAGGGTCCAGGGAAGGGACTGGAGTGGGTCGCAACGATAAGTACGAGTACTGCTGGCTCATACTACGCAGACTCCGTGAGGGGCCGGTTCACCATCTCTAGAGACAATTCCAAGAACACGTTATATCTGCAAATGAACAGTCTGAGAGTCGAAGACACGGCCGTATATTACTGTGCGAGAGATCAGGAAGTGGAACTGATCGATGATGCTTTTGATTTCTGGGGCCGGGGGACAATGGTCACCGTCTCTTCA 255 4066 370EVQLLESGGALVEPGGSLRLSCAASGFSFNTYSMNWVRQGPGKGLEWVATISTSTAGSYYADSVRGRFTISRDNSKNTLYLQMNSLRVEDTAVYYCARDQEVELIDDAFDFWGRGTMVTVSS 255 4067 371 FSFNTYSMN 255 4068 372TTCTCCTTTAACACGTATTCCATGAAC 255 4069 373 TISTSTAGSYYADSVRG 255 4070 374ACGATAAGTACGAGTACTGCTGGCTCATACTACGCAGACTCCGTGAG GGGC 255 4071 375ARDQEVELIDDAFDF 255 4072 376GCGAGAGATCAGGAAGTGGAACTGATCGATGATGCTTTTGATTTC 255 4073 377GATATTGTGATGACTCAGACACATTCCTCCCTGTCTGCATCTGTGGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTATCTGGGTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGACTCTGCAACTTATTACTGCCAACAGTATTACACCTATTACAGTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 255 4074 378DIVMTQTHSSLSASVGDRVTITCRASQSISIWVAWYQQKPGKAPNLLIYKASSLQSGVPSRFSGSGSGTEFTLTISSLQPDDSATYYCQQYYTYYSFGQGT KLEIK 255 4075 379RASQSISIWVA 255 4076 380 CGGGCCAGTCAGAGTATTAGTATCTGGGTGGCC 255 4077 381KASSLQS 255 4078 382 AAGGCGTCTAGTTTACAAAGT 255 4079 383 QQYYTYYS 2554080 384 CAACAGTATTACACCTATTACAGT 256 4081 385GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAAGAGGCCTGGGGCCTCAGTGAAAATCTCCTGCAAGGCTTCTGAATACGCCTTCACCGCCCACTATCTTCACTGGGTGCGACAGGCCCCTGATCAAGGACTTGAGTGGATGGGATGGATCAGCCCTAAAAGTGGTGGCACCAACTATGCACAGAAGTTTCACGGCAGGGTCAGCATGACCAGTGACACGTCCATCAGTACAGTCTATATGGAACTGAGCAGCCTGACATCTGACGACACGGCCGTCTATTACTGTGCGAGAAGCAGTCTGGTGGGAGCAAGCCCCAACTTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 256 4082 386EVQLVESGAEVKRPGASVKISCKASEYAFTAHYLHWVRQAPDQGLEWMGWISPKSGGTNYAQKFHGRVSMTSDTSISTVYMELSSLTSDDTAVYYCARSSLVGASPNFDFWGQGTLVTVSS 256 4083 387 YAFTAHYLH 256 4084 388TACGCCTTCACCGCCCACTATCTTCAC 256 4085 389 WISPKSGGTNYAQKFHG 256 4086 390TGGATCAGCCCTAAAAGTGGTGGCACCAACTATGCACAGAAGTTTCA CGGC 256 4087 391ARSSLVGASPNFDF 256 4088 392 GCGAGAAGCAGTCTGGTGGGAGCAAGCCCCAACTTTGACTTC256 4089 393 CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAACTCCCAGGAACTACCCCCAAAGTCCTCATTTACGACAATAATCAGCGACCCTCAGGGATTCCTGACCGTTTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGCCATCAGCGGACTCCAGACTGGCGACGAGGCCGTCTATTATTGCGGAACATGGGATGCCAGCCTGAGTGCTGCTATGGTTTTCGGCGGGGGGACCAAGCTCACCGTCCTA 256 4090 394QSVLTQPPSVSAAPGQRVTISCSGSSSNIGNNYVSWYQQLPGTTPKVLIYDNNQRPSGIPDRFSGSKSGTSATLAISGLQTGDEAVYYCGTWDASLSAAM VFGGGTKLTVL 256 4091395 SGSSSNIGNNYVS 256 4092 396 TCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCC256 4093 397 DNNQRPS 256 4094 398 GACAATAATCAGCGACCCTCA 256 4095 399GTWDASLSAAMV 256 4096 400 GGAACATGGGATGCCAGCCTGAGTGCTGCTATGGTT 257 4097401 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCGGATATTACTGGAGCTGGATCCGGCAGCCCCCAGGGAGGGGACTGGAGTGGATTGGGTTTATTTATTATAGTGGGAGTACCAGCTACGACTCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCCTAAACCTGAGCTCTGTGACCGCTGCGGACACGGCCGTATATTACTGTGCGAGAAGTACATGGGACTACGGTGACCACTTTCCGTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 257 4098 402QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGRGLEWIGFIYYSGSTSYDSSLKSRVTISVDTSKNQFSLNLSSVTAADTAVYYCARSTWD YGDHFPFDYWGQGTLVTVSS257 4099 403 GSISGYYWS 257 4100 404 GGCTCCATCAGCGGATATTACTGGAGC 257 4101405 FIYYSGSTSYDSSLKS 257 4102 406TTTATTTATTATAGTGGGAGTACCAGCTACGACTCCTCCCTCAAGAGT 257 4103 407ARSTWDYGDHFPFDY 257 4104 408GCGAGAAGTACATGGGACTACGGTGACCACTTTCCGTTTGACTAC 257 4105 409TCCTATGAGCTGACTCAGCCACCCTCAGTGTCAGTGGCCCCAGGAAAGACGGCCAGGATTACCTGTGGGGGAAACAACATTGGAATTAAAGATGTGCACTGGTACCAACTGAGGCCAGGCCAGGCCCCTGTGTTGGTCATCTCTTATGATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACCATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTTCTGTCAGGTGTGGGATAGTAGTCCTGATCATCCTTATGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA 257 4106 410SYELTQPPSVSVAPGKTARITCGGNNIGIKDVHWYQLRPGQAPVLVISYDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYFCQVWDSSPDHPYVF GTGTKLTVL 257 4107411 GGNNIGIKDVH 257 4108 412 GGGGGAAACAACATTGGAATTAAAGATGTGCAC 257 4109413 YDSDRPS 257 4110 414 TATGATAGCGACCGGCCCTCA 257 4111 415 QVWDSSPDHPYV257 4112 416 CAGGTGTGGGATAGTAGTCCTGATCATCCTTATGTC 258 4113 417GAGGTGCAGCTGGTGGAGTCTGGAGGTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAGGGCCTCTGGTTACACCTTTAGAAACTATGGCCTCACCTGGGTGCGGCAGGCCCCCGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAATGGAAACACAAACTATGCACAGAAGTTCCAGGGCAGAGTCACACTGACCACGGACACATCCACGAGCACAGCCTACATGGAACTGAGGAGCCTAAGATCTGACGACACGGCCGTGTATTTCTGTGCGAGAGACGTCCCCGGCCACGGCGCTGCCTTCATGGACGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCA 258 4114 418EVQLVESGGEVKKPGASVKVSCRASGYTFRNYGLTWVRQAPGQGLEWMGWISAYNGNTNYAQKFQGRVTLTTDTSTSTAYMELRSLRSDDTAVYFCARDVPGHGAAFMDVWGTGTTVTVSS 258 4115 419 YTFRNYGLT 258 4116 420TACACCTTTAGAAACTATGGCCTCACC 258 4117 421 WISAYNGNTNYAQKFQG 258 4118 422TGGATCAGCGCTTACAATGGAAACACAAACTATGCACAGAAGTTCCA GGGC 258 4119 423ARDVPGHGAAFMDV 258 4120 424 GCGAGAGACGTCCCCGGCCACGGCGCTGCCTTCATGGACGTC258 4121 425 GAAACGACACTCACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGGCAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAAGCCAGTGATACAAATATCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGATTTCTAACCGAGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTCATTTCACACTGAGAATCAGCAGGGTGGAGGCTGACGATGTTGCGGTTTATTACTGCATGCAGGGTACACACTGGCCTCCGGCGTTCGGCCAGGGGACCAAGCTGGAGATC AAA 258 4122 426ETTLTQSPLSLPVTLGQPASISCRSSQSLEASDTNIYLSWFQQRPGQSPRRLIYKISNRDSGVPDRFSGSGSGTHFTLRISRVEADDVAVYYCMQGTHWPPA FGQGTKLEIK 258 4123427 RSSQSLEASDTNIYLS 258 4124 428AGGTCTAGTCAAAGCCTCGAAGCCAGTGATACAAATATCTACTTGAG T 258 4125 429 KISNRDS258 4126 430 AAGATTTCTAACCGAGACTCT 258 4127 431 MQGTHWPPA 258 4128 432ATGCAGGGTACACACTGGCCTCCGGCG 259 4129 433GAGGTGCAGCTGGTGGAGTCTGGATCTGAGGTGAAGAAGCCTGGGGCCGCAGTGAAGGTATCCTGCAAGGCTTCTGGTTACATCTTTGCCAACTTTGGTGTCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGTTCCAGGGCAGAGTCATCATGACCACAGACACATCCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTATTGTGCGAGAGACCCCCCCGCCTACGCCGCTACATTGATGGACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCA 259 4130 434EVQLVESGSEVKKPGAAVKVSCKASGYIFANFGVSWVRQAPGQGLEWMGWISAYNGNTNYAQKFQGRVIMTTDTSTSTAYMELRSLRSDDTAVYYCARDPPAYAATLMDVWGKGTTVTVSS 259 4131 435 YIFANFGVS 259 4132 436TACATCTTTGCCAACTTTGGTGTCAGC 259 4133 437 WISAYNGNTNYAQKFQG 259 4134 438TGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGTTCCA GGGC 259 4135 439ARDPPAYAATLMDV 259 4136 440 GCGAGAGACCCCCCCGCCTACGCCGCTACATTGATGGACGTC259 4137 441 GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGTCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAACACAGTGATACAAACACCTACTTGACTTGGTATCAGCAGAGGCCAGGCCAATCTCCAAGGCGGCTACTTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGTACACACTGGCCTCCGACGTTCGGCCAAGGGACCAAGCTGGAGAT CAAA 259 4138 442DIVMTQSPLSLPVTLGQSASISCRSSQSLEHSDTNTYLTWYQQRPGQSPRRLLYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGTHWP PTFGQGTKLEIK 259 4139443 RSSQSLEHSDTNTYLT 259 4140 444AGGTCTAGTCAAAGCCTCGAACACAGTGATACAAACACCTACTTGAC T 259 4141 445 KVSNRDS259 4142 446 AAGGTTTCTAACCGGGACTCT 259 4143 447 MQGTHWPPT 259 4144 448ATGCAAGGTACACACTGGCCTCCGACG 260 4145 449GAGGTGCAGCTGGTGGAGTCTGGCCCAACACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGTTGTCTCTGGTGGCTCCGTCTACAGGAGTAGTAACTACTGGGCCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATCGGGAGTGTCTATCATAGTGGGAACCCCTACTCCAACCCGTCCCTTCAGAGTCGAGTCTCCGTCTCCATTGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGTACTCTGTGACCGCCGCAGACTCGGCTATTTATTATTGTGCGTGTAAAAGAGCGGACGCTGACGACGTAGATTACGTGGCGGGCCTCACCGGTTTCCCCTGGTACTTCGATGTCTGGGGCCGTGGCAC CCTGGTCACCGTCTCCTCA 2604146 450 EVQLVESGPTLVKPSETLSLTCVVSGGSVYRSSNYWAWIRQPPGKGLEWIGSVYHSGNPYSNPSLQSRVSVSIDTSKNQFSLKLYSVTAADSAIYYCACKRADADDVDYVAGLTGFPWYFDVWGRGTLVTVSS 260 4147 451 GSVYRSSNYWA 260 4148 452GGCTCCGTCTACAGGAGTAGTAACTACTGGGCC 260 4149 453 SVYHSGNPYSNPSLQS 260 4150454 AGTGTCTATCATAGTGGGAACCCCTACTCCAACCCGTCCCTTCAGAGT 260 4151 455ACKRADADDVDYVAGLTGFPWYFDV 260 4152 456GCGTGTAAAAGAGCGGACGCTGACGACGTAGATTACGTGGCGGGCCTCACCGGTTTCCCCTGGTACTTCGATGTC 260 4153 457GAAATTGTGTTGACGCAGTCTCCGTCCACCCTGTCTGCATCTGTGGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGTTGGTTGGCCTGGTATCAGCAGAAACCAGGGAAAACCCCTAAGTTGCTCATCTATAAGGCGTCTACTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGCGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTCGCAACCTACTACTGCCAACAGTATCATGTTTATTTCCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA 260 4154 458EIVLTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKTPKLLIYKASTLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYHVYFPLTFGGG TKVEIK 260 4155 459RASQSISSWLA 260 4156 460 CGGGCCAGTCAGAGTATTAGTAGTTGGTTGGCC 260 4157 461KASTLES 260 4158 462 AAGGCGTCTACTTTAGAAAGT 260 4159 463 QQYHVYFPLT 2604160 464 CAACAGTATCATGTTTATTTCCCGCTCACT 261 4161 465GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGTAGCGTCTGGATTCAGCTTCAGTATGCATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGACAGCTATATGGTATGATGGAAGTAATAAATATTATGCAGACTCCGTGAAGGGCCGATTCACGATCTCCAGAGACAATTCTAGGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCATGCCTCAACTCCATACTACATGGACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCTTCA 261 4162 466EVQLVESGGGVVQPGRSLRLSCVASGFSFSMHGMHWVRQAPGKGLEWVTAIWYDGSNKYYADSVKGRFTISRDNSRNTLYLQMNSLRAEDTAVYYCARDHASTPYYMDVWGKGTTVTVSS 261 4163 467 FSFSMHGMH 261 4164 468TTCAGCTTCAGTATGCATGGCATGCAC 261 4165 469 AIWYDGSNKYYADSVKG 261 4166 470GCTATATGGTATGATGGAAGTAATAAATATTATGCAGACTCCGTGAA GGGC 261 4167 471ARDHASTPYYMDV 261 4168 472 GCGAGAGATCATGCCTCAACTCCATACTACATGGACGTC 2614169 473 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGCGCCACCCTCTCCTGCAGGACCAGTCAGAGGATTAGCAGCACCTACTTAGCCTGGTACCGGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATGTATGGTGCATCCAGCAGGGCCACTGGCATCCCGGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGTCTGGAGCCTGAAGATTTTGCACTATATTACTGTCAGCAGTATGGTAGCTTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 261 4170 474ETTLTQSPGTLSLSPGESATLSCRTSQRISSTYLAWYRQKPGQAPRLLMYGASSRATGIPDRFSGSGSGTDFTLTISSLEPEDFALYYCQQYGSFPWTFGQ GTKVEIK 261 4171 475RTSQRISSTYLA 261 4172 476 AGGACCAGTCAGAGGATTAGCAGCACCTACTTAGCC 261 4173477 GASSRAT 261 4174 478 GGTGCATCCAGCAGGGCCACT 261 4175 479 QQYGSFPWT261 4176 480 CAGCAGTATGGTAGCTTTCCGTGGACG 262 4177 481CAGGTCCAGCTGGTGCAGTCTGGGCCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGTTATGCTATCACGTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGGGGGATCATCCCTTCCTTTGATAGAGTGGACTATTCACGGAACTTCAAGGGGAGAGTCACCTTTACCGCGGACAAATCCGCGAACACGGCCTACATGGAACTGACCAATGTGAGATCCGACGACACGGCCGTGTATTACTGTGCGAGAGGCTGTTGTGGGGCTGTGGCTGGATTCCAGCACTGGGGCCAGGGCACCGGGGTCACCGTCTCCTCA 262 4178 482QVQLVQSGPEVKKPGSSVKVSCKASGGTFSSYAITWVRQAPGQGLEWMGGIIPSFDRVDYSRNFKGRVTFTADKSANTAYMELTNVRSDDTAVYYCARGCCGAVAGFQHWGQGTGVTVSS 262 4179 483 GTFSSYAIT 262 4180 484GGCACCTTCAGCAGTTATGCTATCACG 262 4181 485 GIIPSFDRVDYSRNFKG 262 4182 486GGGATCATCCCTTCCTTTGATAGAGTGGACTATTCACGGAACTTCAAG GGG 262 4183 487ARGCCGAVAGFQH 262 4184 488 GCGAGAGGCTGTTGTGGGGCTGTGGCTGGATTCCAGCAC 2624185 489 GATATTGTGCTGACGCAGACTCCAGCCACCCTGTCTTTATCTCCAGGGGAAACAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTACCACCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCGTCCCAACCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGGAGCCTGAAGATTATGCGATTTATTACTGTCAGCAACGTACTACCGGGGTCACTTTCGGCGGGGGGACCAAGGTGGAAATCAAA 262 4186 490DIVLTQTPATLSLSPGETATLSCRASQSVTTYLAWYQQKPGQAPRLLIYDASNRATGVPTRFSGSGSGTDFTLTISSLEPEDYAIYYCQQRTTGVTFGGGT KVEIK 262 4187 491RASQSVTTYLA 262 4188 492 AGGGCCAGTCAGAGTGTTACCACCTACTTAGCC 262 4189 493DASNRAT 262 4190 494 GATGCATCCAACAGGGCCACT 262 4191 495 QQRTTGVT 2624192 496 CAGCAACGTACTACCGGGGTCACT 263 4193 497CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCTTGTGCAGCCTCTGGATTCACCTTCAGTAGTTTTGGCATGCATTGGGTCCGCCAGGCTCCAGGGCAGGGACTGGAGTGGGTCGCATCCATTACTGGTGGCAGCAGTTACATAAACTACGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAAGTCACTGTCTCTGCAAATGAAGAACCTGAGAGCCGAGGACACGGCTGAGTATTACTGTGTGCGAGGAGTCCTACCAGGTGGTACTGGGGGGGGCTGGTTCGACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 263 4194 498QVQLVESGGGLVKPGGSLRLSCAASGFTFSSFGMHWVRQAPGQGLEWVASITGGSSYINYADSVKGRFTISRDNAKKSLSLQMKNLRAEDTAEYYCVRGVLPGGTGGGWFDSWGQGTLVTVSS 263 4195 499 FTFSSFGMH 263 4196 500TTCACCTTCAGTAGTTTTGGCATGCAT 263 4197 501 SITGGSSYINYADSVKG 263 4198 502TCCATTACTGGTGGCAGCAGTTACATAAACTACGCAGACTCAGTGAA GGGC 263 4199 503VRGVLPGGTGGGWFDS 263 4200 504GTGCGAGGAGTCCTACCAGGTGGTACTGGGGGGGGCTGGTTCGACTC C 263 4201 505CAGTCTGTCCTGACTCAGCCGCCCTCAATGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGACCAGCTCCAACATCGGGGCGGGTTATGATGTACAGTGGTATCAGCAGTTTCCAGGAACAGCCCCCAAACTCCTCATCTCTGGTAACAACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCGCCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACTACAGCCTGAATTGGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 263 4202 506QSVLTQPPSMSGAPGQRVTISCTGTSSNIGAGYDVQWYQQFPGTAPKLLISGNNNRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDYSLNW VFGGGTKLTVL 263 4203507 TGTSSNIGAGYDVQ 263 4204 508ACTGGGACCAGCTCCAACATCGGGGCGGGTTATGATGTACAG 263 4205 509 GNNNRPS 263 4206510 GGTAACAACAATCGGCCCTCA 263 4207 511 QSYDYSLNWV 263 4208 512CAGTCCTATGACTACAGCCTGAATTGGGTG 264 4209 513CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCGCTCACCTGCACTGTCTCTGGTCGCTTCCTCAATAGTGGTGATTACTACTGGAGTTGGATCCGCCAGTCCCCAGGGAAGGGCCTGGAGTGGCTTGGTTACATCCATCACAGTGGGAACACCTACTACAACCCGTCCCTCAAGAGTCGACTTACCATATCACTAGACATGTCCAAGAACCAGTTCTCCCTGAAGTTGAGCTCTGTGACAGCCGCAGACACGGCCGTCTATTACTGTGCCAGAGATTTGGGAAAGCCGCTTTGGGACGGCCACTATTACTACGGAGTGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCT CA 264 4210 514QVQLQESGPGLVKPSQTLSLTCTVSGRFLNSGDYYWSWIRQSPGKGLEWLGYIHHSGNTYYNPSLKSRLTISLDMSKNQFSLKLSSVTAADTAVYYCARDLGKPLWDGHYYYGVDVWGQGTTVTVSS 264 4211 515 RFLNSGDYYWS 264 4212 516CGCTTCCTCAATAGTGGTGATTACTACTGGAGT 264 4213 517 YIHHSGNTYYNPSLKS 264 4214518 TACATCCATCACAGTGGGAACACCTACTACAACCCGTCCCTCAAGAG T 264 4215 519ARDLGKPLWDGHYYYGVDV 264 4216 520GCCAGAGATTTGGGAAAGCCGCTTTGGGACGGCCACTATTACTACGG AGTGGACGTC 264 4217 521GATATTGTGATGACTCAGTCTCCAGGCACTCTGTCTTTGTCTCCAGGAGAAAGAGCCACCCTCTCCTGCAGGACCAGTCAGAATGTTAACAGCAACTACTTAGCCTGGTACCAGCATAAACCTGGGCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGTCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCACCAGAGTGGAGTCTGAAGATTTTGCAGTGTATTACTGTCAGGTGTATAGTAGTTCACCTCCGATCACCTTCGGCCAGGGGACCAAGGTGGAGATCAAA 264 4218 522DIVMTQSPGTLSLSPGERATLSCRTSQNVNSNYLAWYQHKPGQAPRLLIYGASSRVTGIPDRFSGSGSGTDFTLTITRVESEDFAVYYCQVYSSSPPITFGQ GTKVEIK 264 4219523 RTSQNVNSNYLA 264 4220 524 AGGACCAGTCAGAATGTTAACAGCAACTACTTAGCC 2644221 525 GASSRVT 264 4222 526 GGTGCATCCAGCAGGGTCACT 264 4223 527QVYSSSPPIT 264 4224 528 CAGGTGTATAGTAGTTCACCTCCGATCACC 265 4225 529CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGTTATGCTATCAGCTGGGTGCGTCAGGCCCCAGGACAAGGGCTTGAGTGGATGGGAGGAATCATCCCTATGTTTGATATAGTCGACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAACACAGCCTACATGGAGCTGACCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAACTGCGGCTTTAGGACCACCTGGGACTATAGTGGGGTACATGGACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCA 265 4226 530QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPMFDIVDYAQKFQGRVTITADESTNTAYMELTSLRSEDTAVYYCARTAALGPPGTIVGYMDVWGKGTTVTVSS 265 4227 531 GTFSSYAIS 265 4228 532GGCACCTTCAGCAGTTATGCTATCAGC 265 4229 533 GIIPMFDIVDYAQKFQG 265 4230 534GGAATCATCCCTATGTTTGATATAGTCGACTACGCACAGAAGTTCCAG GGC 265 4231 535ARTAALGPPGTIVGYMDV 265 4232 536GCGAGAACTGCGGCTTTAGGACCACCTGGGACTATAGTGGGGTACAT GGACGTC 265 4233 537GATATTGTGATGACGCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCCGGTCTAGTCAGAGCCTCCTGCAAAGTAATGGATACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGGCTCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAAGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAACTCTACAAACTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAAT CAAA 265 4234 538DIVMTQSPLSLPVTPGEPASISCRSSQSLLQSNGYNYLDWYLQKPGQAPQLLIYLGSNRASGVPDKFSGSGSGTDFTLKISRVEAEDVGVYYCMQTLQTP WTFGQGTKVEIK 265 4235539 RSSQSLLQSNGYNYLD 265 4236 540CGGTCTAGTCAGAGCCTCCTGCAAAGTAATGGATACAACTATTTGGAT 265 4237 541 LGSNRAS265 4238 542 TTGGGTTCTAATCGGGCCTCC 265 4239 543 MQTLQTPWT 265 4240 544ATGCAAACTCTACAAACTCCGTGGACG 266 4241 545CAGGTGCAGCTGGTGGAGTCTGGAGCAGAGGCGAGAAAGCCCGGGGAGTCTCTGAAGATCTCCTGTAAGGCTTCTGGATACAGCTTTACCAATTATTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGGGGTCATCTATCCTGCTGACTCCGATACCAGATATAGCCCGTCCTTCAAAGGCCAGGTCACCATCTCAGCCGACAAATCCATCAGCACCGCCTACCTCCAGTGGACCAGACTGAAGGCCTCGGACACCGCCGTGTATTTCTGTGCGAGACTTGGAATAGGAGCTGCTGCCCGGAACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCA 266 4242 546QVQLVESGAEARKPGESLKISCKASGYSFTNYWIGWVRQMPGKGLEWMGVIYPADSDTRYSPSFKGQVTISADKSISTAYLQWTRLKASDTAVYFCAR LGIGAAARNYWGQGTLVTVSS266 4243 547 YSFTNYWIG 266 4244 548 TACAGCTTTACCAATTATTGGATCGGC 266 4245549 VIYPADSDTRYSPSFKG 266 4246 550GTCATCTATCCTGCTGACTCCGATACCAGATATAGCCCGTCCTTCAAA GGC 266 4247 551ARLGIGAAARNY 266 4248 552 GCGAGACTTGGAATAGGAGCTGCTGCCCGGAACTAC 266 4249553 GACATCCAGGTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCGACAGTTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTACGATGCATCCAAGTCGGAAACAGGGGTCCCATCAAGATTCAGTGGAAGCGGATCTGGGACAGATTTCACTTTCACCATCAGTAGCCTGCAGCCTGAAGATCTTGCAACATATTACTGTCTACAGTTTGATAATCTCCCTCCGACCTTCGGCCAAGGGACACGACTGGAGATTAAA 266 4250 554DIQVTQSPSSLSASVGDRVTITCQASQDISDSLNWYQQKPGKAPNLLIYDASKSETGVPSRFSGSGSGTDFTFTISSLQPEDLATYYCLQFDNLPPTFGQG TRLEIK 266 4251 555QASQDISDSLN 266 4252 556 CAGGCGAGTCAGGACATTAGCGACAGTTTAAAT 266 4253 557DASKSET 266 4254 558 GATGCATCCAAGTCGGAAACA 266 4255 559 LQFDNLPPT 2664256 560 CTACAGTTTGATAATCTCCCTCCGACC 267 4257 561GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTAGTAGTAGTAATTACATAAACTACGCAGACTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGATTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA 267 4258 562EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWVSSISSSSNYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCARDLLPVERGPAFDIWGQGTMVTVSS 267 4259 563 FSFRSYSMN 267 4260 564TTCAGCTTCAGGAGCTATAGCATGAAC 267 4261 565 SISSSSNYINYADSVKG 267 4262 566TCCATTAGTAGTAGTAGTAATTACATAAACTACGCAGACTCAGTGAA GGGC 267 4263 567ARDLLPVERGPAFDI 267 4264 568GCGAGAGATTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATATC 267 4265 569TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCATCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTTCGGTATTCGGCGGAGGGACCAAGGTGACCGTCCT A 267 4266 570SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQQLPGAAPKLLIYANSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGS VFGGGTKVTVL 267 4267571 TGSSSNIGAGYDVH 267 4268 572ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 267 4269 573 ANSNRPS 267 4270574 GCTAACAGCAATCGGCCCTCA 267 4271 575 QSYDSRLGGSV 267 4272 576CAGTCCTATGACAGCAGACTGGGTGGTTCGGTA 268 4273 577CAGGTCCAGCTTGTGCAGTCTGGACCAGAGGTGAAAAAGCCCGGGGAGTCTCTGACGATCTCCTGTAAGGGTTCTGGATACGACTTTTCCAATAACTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGGAATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCGTTCCAAGGCCAGGTCACCCTCTCAGTCGACAAGTCCATTAGTACCGCCTACCTACAGTGGAGGAGCCTGAAGGCCTCGGACAGCGGCATCTACTACTGTGCGAGACAAATTGGCGGTTTGGTTTGTAGCAGTGAGAGCTGCTACTTCTACGGCATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCT CCTCA 268 4274 578QVQLVQSGPEVKKPGESLTISCKGSGYDFSNNWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTLSVDKSISTAYLQWRSLKASDSGIYYCARQIGGLVCSSESCYFYGMDVWGQGTTVTVSS 268 4275 579 YDFSNNWIG 268 4276 580TACGACTTTTCCAATAACTGGATCGGC 268 4277 581 IIYPGDSDTRYSPSFQG 268 4278 582ATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCGTTCCAA GGC 268 4279 583ARQIGGLVCSSESCYFYGMDV 268 4280 584GCGAGACAAATTGGCGGTTTGGTTTGTAGCAGTGAGAGCTGCTACTTC TACGGCATGGACGTC 2684281 585 GACATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGAGGCAGAGTGACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAACTATTTAAATTGGTATCAACACAAACCGGGGAAAGCCCCTGAACTCCTGATCTATGGTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGACTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTGACACTACCCCGTTCACTTTCGGCCAGGGGACCAAAGTGGATATCAAA 268 4282 586DIQLTQSPSSLSASVGGRVTITCRASQSISNYLNWYQHKPGKAPELLIYGASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSDTTPFTFGQGT KVDIK 268 4283 587RASQSISNYLN 268 4284 588 CGGGCAAGTCAGAGCATTAGCAACTATTTAAAT 268 4285 589GASSLQS 268 4286 590 GGTGCATCCAGTTTGCAAAGT 268 4287 591 QQSDTTPFT 2684288 592 CAACAGAGTGACACTACCCCGTTCACT 269 4289 593CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCTTGGTAAAGCCGGGGGGGTCCCTTAGACTCTCCTGTGCAGCCTCTGGATTCACTTTCAGTAAGGCCTGGATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTGGCCGTATTAGAAGCAAAACTGATGGTGGGACAGCAGACTACGCGGCACCCGTGAAAGGCAGATTCACCATGTCAAGAGATGATTCAAAAAACACGCTGTATTTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTGCCACAGATTCTCGCCGACTCTATGATAGTCGTGGTTTTTATTCAAGTGCTTTTGATGTCTGGGGCCAAGGGACCACGGTCACCG TCTCCTCA 269 4290 594QVQLVQSGGGLVKPGGSLRLSCAASGFTFSKAWMNWVRQAPGKGLEWVGRIRSKTDGGTADYAAPVKGRFTMSRDDSKNTLYLQMNSLKTEDTAVYYCATDSRRLYDSRGFYSSAFDVWGQGTTVTVSS 269 4291 595 FTFSKAWMN 269 4292 596TTCACTTTCAGTAAGGCCTGGATGAAC 269 4293 597 RIRSKTDGGTADYAAPVKG 269 4294598 CGTATTAGAAGCAAAACTGATGGTGGGACAGCAGACTACGCGGCACC CGTGAAAGGC 269 4295599 ATDSRRLYDSRGFYSSAFDV 269 4296 600GCCACAGATTCTCGCCGACTCTATGATAGTCGTGGTTTTTATTCAAGT GCTTTTGATGTC 269 4297601 CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCGGGTTATGATGTACACTGGTACCAACACCTTCCAGGAACAGCCCCCAAAGTCCTCATCTATGGTAACAACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACGACAGCCTGACTGGTTGGGTGTTCGGCGGAGGGACCAAGGTCACCGTCCT A 269 4298 602QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQHLPGTAPKVLIYGNNNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDDSLTG WVFGGGTKVTVL 269 4299603 TGSSSNIGAGYDVH 269 4300 604ACTGGGAGCAGCTCCAACATCGGGGCGGGTTATGATGTACAC 269 4301 605 GNNNRPS 269 4302606 GGTAACAACAATCGGCCCTCA 269 4303 607 QSYDDSLTGWV 269 4304 608CAGTCCTATGACGACAGCCTGACTGGTTGGGTG 270 4305 609CAGGTGCAGCTGGTGCAATCTGGACCAGAGGTGAAAAAGCCCGGGGAGTCTCTGACGATCTCCTGTAAGGGTTCTGGATACGACTTTTCCAATAACTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGGAATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCGTTCCAAGGCCAGGTCACCCTCTCAGTCGACAAGTCCATTAGTACCGCCTACCTACAGTGGAGGAGCCTGAAGGCCTCGGACAGCGGCATCTACTACTGTGCGAGACAAATTGGCGGTTTGGTTTGTAGCAGTGAGAGCTGCTACTTCTACGGCATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTC TCCTCA 270 4306 610QVQLVQSGPEVKKPGESLTISCKGSGYDFSNNWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTLSVDKSISTAYLQWRSLKASDSGIYYCARQIGGLVCSSESCYFYGMDVWGQGTTVTVSS 270 4307 611 YDFSNNWIG 270 4308 612TACGACTTTTCCAATAACTGGATCGGC 270 4309 613 IIYPGDSDTRYSPSFQG 270 4310 614ATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCGTTCCAA GGC 270 4311 615ARQIGGLVCSSESCYFYGMDV 270 4312 616GCGAGACAAATTGGCGGTTTGGTTTGTAGCAGTGAGAGCTGCTACTTC TACGGCATGGACGTC 2704313 617 GACATCCGGGTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGAGGCAGAGTGACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAACTATTTAAATTGGTATCAACACAAACCGGGGAAAGCCCCTGAACTCCTGATCTATGGTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGACTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTGACACTACCCCGTTCACTTTCGGCCAGGGGACCAAGCTGGAGATCAAA 270 4314 618DIRVTQSPSSLSASVGGRVTITCRASQSISNYLNWYQHKPGKAPELLIYGASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSDTTPFTFGQGT KLEIK 270 4315 619RASQSISNYLN 270 4316 620 CGGGCAAGTCAGAGCATTAGCAACTATTTAAAT 270 4317 621GASSLQS 270 4318 622 GGTGCATCCAGTTTGCAAAGT 270 4319 623 QQSDTTPFT 2704320 624 CAACAGAGTGACACTACCCCGTTCACT 271 4321 625GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCTTGTGCAGCCTCTGGATTCACCTTCAGTAGTTTTGGCATGCATTGGGTCCGCCAGGCTCCAGGGCAGGGACTGGAGTGGGTCGCATCCATTACTGGTGGCAGCAGTTACATAAACTACGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAAGTCACTGTCTCTGCAAATGAAGAACCTGAGAGCCGAGGACACGGCTGAGTATTACTGTGTGCGAGGAGTCCTACCAGGTGATACTGGGGGGGGCTGGTTCGACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 271 4322 626EVQLVESGGGLVKPGGSLRLSCAASGFTFSSFGMHWVRQAPGQGLEWVASITGGSSYINYADSVKGRFTISRDNAKKSLSLQMKNLRAEDTAEYYCVRGVLPGDTGGGWFDSWGQGTLVTVSS 271 4323 627 FTFSSFGMH 271 4324 628TTCACCTTCAGTAGTTTTGGCATGCAT 271 4325 629 SITGGSSYINYADSVKG 271 4326 630TCCATTACTGGTGGCAGCAGTTACATAAACTACGCAGACTCAGTGAA GGGC 271 4327 631VRGVLPGDTGGGWFDS 271 4328 632GTGCGAGGAGTCCTACCAGGTGATACTGGGGGGGGCTGGTTCGACTC C 271 4329 633CAGTCTGTGCTGACGCAGCCGCCCTCAATGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGACCAGCTCCAACATCGGGGCGGGTTATGATGTACAGTGGTATCAGCAGTTTCCAGGAACAGCCCCCAAACTCCTCATCTCTGGTAACAACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCGCCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACTACAGCCTGAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA 271 4330 634QSVLTQPPSMSGAPGQRVTISCTGTSSNIGAGYDVQWYQQFPGTAPKLLISGNNNRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDYSLNW VFGGGTKLTVL 271 4331635 TGTSSNIGAGYDVQ 271 4332 636ACTGGGACCAGCTCCAACATCGGGGCGGGTTATGATGTACAG 271 4333 637 GNNNRPS 271 4334638 GGTAACAACAATCGGCCCTCA 271 4335 639 QSYDYSLNWV 271 4336 640CAGTCCTATGACTACAGCCTGAATTGGGTG 272 4337 641CAGGTCCAGCTTGTACAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTAGCAGTTTCTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGGCATCATATATCCTGGTGACTCTGATACCAGATATAGCCCGTCTTTCCAAGGCCAGGTCACCATGTCAGCCGACACGTCCATAAACACCGCCTACCTGCAGTGGAACAGCGTGAAGGCCTCGGACACCGCCATTTATTACTGTGCGAGACTTCCAGTTGGTAGTTATTATTACTTCAATCTCTGGGGCCGTGGCACCCTGGTCACCGTCTCCTCA 272 4338 642QVQLVQSGAEVKKPGESLKISCKGSGYSFSSFWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTMSADTSINTAYLQWNSVKASDTAIYYCARLPVGSYYYFNLWGRGTLVTVSS 272 4339 643 YSFSSFWIG 272 4340 644TACAGCTTTAGCAGTTTCTGGATCGGC 272 4341 645 IIYPGDSDTRYSPSFQG 272 4342 646ATCATATATCCTGGTGACTCTGATACCAGATATAGCCCGTCTTTCCAA GGC 272 4343 647ARLPVGSYYYFNL 272 4344 648 GCGAGACTTCCAGTTGGTAGTTATTATTACTTCAATCTC 2724345 649 GAAATTGTGATGACACAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGCGCCACCCTATTTTGCAGGGCCAGTCAGAGTATTAGTAGCGACTTAGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCACCAGGGCCACTGGTGTCCCTGCCAGGTTCAGTGCCACTGGGTCTGAGGCAGAGTTCACTCTCACCATCAGCGGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCTTTCGTGGACGTTCGGCCAAGGGACCAAGCTGGAGATCAAA 272 4346 650EIVMTQSPATLSVSPGESATLFCRASQSISSDLAWYQQRPGQAPRLLIYDASTRATGVPARFSATGSEAEFTLTISGLQSEDFAVYYCQQYNNWLSWTFG QGTKLEIK 272 4347 651RASQSISSDLA 272 4348 652 AGGGCCAGTCAGAGTATTAGTAGCGACTTAGCC 272 4349 653DASTRAT 272 4350 654 GATGCATCCACCAGGGCCACT 272 4351 655 QQYNNWLSWT 2724352 656 CAGCAGTATAATAACTGGCTTTCGTGGACG 273 4353 657CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGAGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTCGTGGCTCCATCAGAATTGGTGGTTACTTCTGGAGTTGGATCCGCCAGCACCCAGGGAAGGGTCTGGAGTGGCTTGGATACATCTCTAACGATGGGGCCACCGACTACAACCCGTCCCTCAGGAGTCGACTTGCCATATCAGCAGACACATCTAAGAACCAGTTTTCCCTGACCCTGAGGTCTGTGACTGCCGCGGACACGGCCATCTATTACTGTGCGAGAACTTCTTATGCAGGGCGCATGCTCGACCGCTGGGGCCAGGGAATCCTGGTCACCGTCTCCTCA 273 4354 658QVQLQESGPGLEKPSQTLSLTCTVSRGSIRIGGYFWSWIRQHPGKGLEWLGYISNDGATDYNPSLRSRLAISADTSKNQFSLTLRSVTAADTAIYYCARTS YAGRMLDRWGQGILVTVSS273 4355 659 GSIRIGGYFWS 273 4356 660 GGCTCCATCAGAATTGGTGGTTACTTCTGGAGT273 4357 661 YISNDGATDYNPSLRS 273 4358 662TACATCTCTAACGATGGGGCCACCGACTACAACCCGTCCCTCAGGAG T 273 4359 663ARTSYAGRMLDR 273 4360 664 GCGAGAACTTCTTATGCAGGGCGCATGCTCGACCGC 273 4361665 GACATCCGGGTGACCCAGTCTCCAGTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGTCTCCTGCATAGTAATGGAAACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAACTCCTGATCTATATGGGTTCTTATCGGGCCTCCGGGGTCCCTGACAGGTTCAGCGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGTGTTTATTACTGCATGCAAGGTCTACAAATTCCTTGGACGTTCGGCCAAGGGACCAAGCTGGAGAT CAAA 273 4362 666DIRVTQSPVSLPVTPGEPASISCRSSQSLLHSNGNNYLDWYLQKPGQSPQLLIYMGSYRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGLQIP WTFGQGTKLEIK 273 4363667 RSSQSLLHSNGNNYLD 273 4364 668AGGTCTAGTCAGAGTCTCCTGCATAGTAATGGAAACAACTATTTGGAT 273 4365 669 MGSYRAS273 4366 670 ATGGGTTCTTATCGGGCCTCC 273 4367 671 MQGLQIPWT 273 4368 672ATGCAAGGTCTACAAATTCCTTGGACG 274 4369 673GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTCAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATGCCATGCACTGGGTCCGCCAGACTCCAGACAAGGGGCTGGAGTGGGTGGCACTTATATCCGATGATGGAAGAAATGAATATTATGCAGATTCCGTGCAGGGCCGATTCACCATCTCCAGAGACAAATCCAAGAACACGCTGCATCTGGAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTTTATTACTGTGCGAAAGTACGAAATGAGGCGTGGGAGCTCCTGGGTAATGATGATGCTCTTGATGTCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA 274 4370 674EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQTPDKGLEWVALISDDGRNEYYADSVQGRFTISRDKSKNTLHLEMNSLRAEDTAVYYCAKVRNEAWELLGNDDALDVWGQGTMVTVSS 274 4371 675 FTFSSYAMH 274 4372 676TTCACCTTCAGTAGCTATGCCATGCAC 274 4373 677 LISDDGRNEYYADSVQG 274 4374 678CTTATATCCGATGATGGAAGAAATGAATATTATGCAGATTCCGTGCA GGGC 274 4375 679AKVRNEAWELLGNDDALDV 274 4376 680GCGAAAGTACGAAATGAGGCGTGGGAGCTCCTGGGTAATGATGATGC TCTTGATGTC 274 4377 681CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAAGTCACCATCTCCTGCTCTGGAACTAGCTTCAACATTGGCAGTAATTACGTATCCTGGTACCAGCTACTCCCAGGAACAGCCCCCAAACTCCTCATTTTTGACAATTATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCTGGTCTGGCACGTCAGCCACCCTGGCCATCAGCGGACTCCAGACTGGGGACGAGGCCGAATACTTCTGCGGAACTTGGGACACCAGCCTGAGAGCTGGAGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 274 4378 682QSVLTQPPSVSAAPGQKVTISCSGTSFNIGSNYVSWYQLLPGTAPKLLIFDNYKRPSGIPDRFSGSWSGTSATLAISGLQTGDEAEYFCGTWDTSLRAGVF GGGTKLTVL 274 4379683 SGTSFNIGSNYVS 274 4380 684 TCTGGAACTAGCTTCAACATTGGCAGTAATTACGTATCC274 4381 685 DNYKRPS 274 4382 686 GACAATTATAAGCGACCCTCA 274 4383 687GTWDTSLRAGV 274 4384 688 GGAACTTGGGACACCAGCCTGAGAGCTGGAGTG 275 4385 689CAGGTCCAGCTGGTGCAGTCTGGGTCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAGGCTCTCCTGCAAGGTTGCCGGTTACAGCCTCAGTGAGTTATCCATGCACTGGGTGCGACAGTCTCCTGGAAAAGGGCTTGAGTGGTTGGGAGCTTTTGACCATGAAGATGCTGAAGCAATCTATGCACCGAGGTTCCAGGGCAGAATCACCATGACCGCGGACACATCTACGGACACAGCCTACATGGAACTGAGCAGCCTGAGATCTGAGGACACGGCCGTTTATTACTGTGCAACACCGACCCCAGTTGGAGCTACGGACTACTGGGGCCAG GGAACCCTGGTCACCGTCTCCTCA275 4386 690 QVQLVQSGSEVKKPGASVRLSCKVAGYSLSELSMHWVRQSPGKGLEWLGAFDHEDAEAIYAPRFQGRITMTADTSTDTAYMELSSLRSEDTAVYYCA TPTPVGATDYWGQGTLVTVSS275 4387 691 YSLSELSMH 275 4388 692 TACAGCCTCAGTGAGTTATCCATGCAC 275 4389693 AFDHEDAEAIYAPRFQG 275 4390 694GCTTTTGACCATGAAGATGCTGAAGCAATCTATGCACCGAGGTTCCA GGGC 275 4391 695ATPTPVGATDY 275 4392 696 GCAACACCGACCCCAGTTGGAGCTACGGACTAC 275 4393 697GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGTATTAGTAGTTATTTAAATTGGTATCAACAAAAACCAGGAAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGGGGGGGCCCATCAAGATTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTATTGTCAACAGAGTTACATTATTCCGTACACTTTTGGCCAGGGGACCAAAGTGGATATCAAA 275 4394 698DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQRGGPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYIIPYTFGQGT KVDIK 275 4395 699RASQSISSYLN 275 4396 700 CGGGCAAGTCAGAGTATTAGTAGTTATTTAAAT 275 4397 701AASSLQR 275 4398 702 GCTGCATCCAGTTTGCAAAGG 275 4399 703 QQSYIIPYT 2754400 704 CAACAGAGTTACATTATTCCGTACACT 276 4401 705CAGGTGCAGCTGCAGGAGTCCGGCCCAGGACGGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCAGTGTCGCTGATGGCTCAATCAGTAGTGGTCATTACTACTGGGGCTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGCGACAATCCATGATAGTGGGGCCACGTACTACAACCCGTCCCTCCAGAGTCGAGTCACCATATCCGTAGACACGTCCAAGAACCAGTTCTCCCTGAAAGTGAATTCTGTGACCGCCGCAGACACGGCTGTCTATTACTGTGCGAGTCGAAGGGGCAGTGGCTGGTTTTTCGACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 276 4402 706QVQLQESGPGRVKPSETLSLTCSVADGSISSGHYYWGWVRQPPGKGLEWIATIHDSGATYYNPSLQSRVTISVDTSKNQFSLKVNSVTAADTAVYYCAS RRGSGWFFDSWGQGTLVTVSS276 4403 707 GSISSGHYYWG 276 4404 708 GGCTCAATCAGTAGTGGTCATTACTACTGGGGC276 4405 709 TIHDSGATYYNPSLQS 276 4406 710ACAATCCATGATAGTGGGGCCACGTACTACAACCCGTCCCTCCAGAG T 276 4407 711ASRRGSGWFFDS 276 4408 712 GCGAGTCGAAGGGGCAGTGGCTGGTTTTTCGACTCC 276 4409713 GATATTGTGCTGACTCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGTCACCCTCTCCTGCAGGGCCAGTCACAGTGTTAACTACAATTTAGCCTGGTACCAGCAGAAACCTGGTCAGGCTCCCAGGCTCCTCATCTATGGTTCATCTACCAGGGCCACTGGTCTCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAATTTATTACTGTCAGCAGTATAATAACTGGCCTCCGGGAGGCACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA 276 4410 714DIVLTQSPATLSVSPGERVTLSCRASHSVNYNLAWYQQKPGQAPRLLIYGSSTRATGLPARFSGSGSGTEFTLTISSLQSEDFAIYYCQQYNNWPPGGTFG QGTKVEIK 276 4411715 RASHSVNYNLA 276 4412 716 AGGGCCAGTCACAGTGTTAACTACAATTTAGCC 276 4413717 GSSTRAT 276 4414 718 GGTTCATCTACCAGGGCCACT 276 4415 719 QQYNNWPPGGT276 4416 720 CAGCAGTATAATAACTGGCCTCCGGGAGGCACT 277 4417 721GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTAGTAGTAGTAGTTACATATACTACGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATTGGCCGAATAGCAGCTCGTCGCCGAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 277 4418 722EVQLLESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDWPNSSSSPNWFDPWGQGTLVTVSS 277 4419 723 FTFSSYSMN 277 4420 724TTCACCTTCAGTAGCTATAGCATGAAC 277 4421 725 SISSSSSYIYYADSVKG 277 4422 726TCCATTAGTAGTAGTAGTAGTTACATATACTACGCAGACTCAGTGAAG GGC 277 4423 727ARDWPNSSSSPNWFDP 277 4424 728GCGAGAGATTGGCCGAATAGCAGCTCGTCGCCGAACTGGTTCGACCC C 277 4425 729CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTCATCTATGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGCCTGAGTGGTTTTTATGTCTTCGGAACTGGGACCAAGCTCACCGTC CTA 277 4426 730QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGF YVFGTGTKLTVL 277 4427731 TGSSSNIGAGYDVH 277 4428 732ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 277 4429 733 GNSNRPS 277 4430734 GGTAACAGCAATCGGCCCTCA 277 4431 735 QSYDSSLSGFYV 277 4432 736CAGTCCTATGACAGCAGCCTGAGTGGTTTTTATGTC 278 4433 737CAGGTCCAGCTGGTACAGTCTGGGGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAAGATCTCCTGTCAGGGTTCTGGATACAGCTTTAGCAGTTTCTGGATCGTCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGGGAGCATCTATCCTGGTGACTCTGACACCAGATACACCCCGTCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCACCAGCACCGCCTATTTGCAGTGGAACAGCCTGAAGCCCTCGGACACCGCCATGTATTACTGTGCGAGGTGTAGTCTCAGCTGCGACTACTACGGAGTGAACCTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 278 4434 738QVQLVQSGAEVKKPGESLKISCQGSGYSFSSFWIVWVRQMPGKGLEWMGSIYPGDSDTRYTPSFQGQVTISADKSTSTAYLQWNSLKPSDTAMYYCARCSLSCDYYGVNLWGQGTTVTVSS 278 4435 739 YSFSSFWIV 278 4436 740TACAGCTTTAGCAGTTTCTGGATCGTC 278 4437 741 SIYPGDSDTRYTPSFQG 278 4438 742AGCATCTATCCTGGTGACTCTGACACCAGATACACCCCGTCCTTCCAA GGC 278 4439 743ARCSLSCDYYGVNL 278 4440 744 GCGAGGTGTAGTCTCAGCTGCGACTACTACGGAGTGAACCTC278 4441 745 CAGTCTGTGGTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGGAGCAGCTCCAACATCGGGGCACGTTCTGATGTACACTGGTACCAGCAGCTTCCAGGAAAAGCCCCCAAACTCCTCATCTATGGTAACACCAATCGGCCCTTAGGGGTCCCTGACCGATTCTCTGGCTCCACGTCTGGCACCTCAGCCTCCCTGGCCATCTCTGGGCTCCAGGCTGAGGATGAGGGATATTATTACTGTCAGTCCTATGACAGCAGCCTGAGTGGTTTTTATGTCTTCGGAACTGGGACCAAGCTCACCGTC CTA 278 4442 746QSVVTQPPSVSGAPGQRVTISCSGSSSNIGARSDVHWYQQLPGKAPKLLIYGNTNRPLGVPDRFSGSTSGTSASLAISGLQAEDEGYYYCQSYDSSLSGF YVFGTGTKLTVL 278 4443747 SGSSSNIGARSDVH 278 4444 748TCTGGGAGCAGCTCCAACATCGGGGCACGTTCTGATGTACAC 278 4445 749 GNTNRPL 278 4446750 GGTAACACCAATCGGCCCTTA 278 4447 751 QSYDSSLSGFYV 278 4448 752CAGTCCTATGACAGCAGCCTGAGTGGTTTTTATGTC 279 4449 753CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCCCCTTCAGTCTCTATGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCATTTATATCATATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAGTTCCAAGAACACGCTGTATCTGCAAATGGACAGCCTGACACCTGAAGACACGGCTGTGTATTACTGTGCGAAACCTATAGTGGGGCCTACAACGGGTTACTTTGACTACTGGGGCCCGGGAACCCTGGTCACCGTCTCCTCA 279 4450 754QVQLVESGGGVVQPGRSLRLSCAASGFPFSLYAMHWVRQAPGKGLEWVAFISYDGSNKYYADSVKGRFTISRDSSKNTLYLQMDSLTPEDTAVYYCAKPIVGPTTGYFDYWGPGTLVTVSS 279 4451 755 FPFSLYAMH 279 4452 756TTCCCCTTCAGTCTCTATGCCATGCAC 279 4453 757 FISYDGSNKYYADSVKG 279 4454 758TTTATATCATATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAG GGC 279 4455 759AKPIVGPTTGYFDY 279 4456 760 GCGAAACCTATAGTGGGGCCTACAACGGGTTACTTTGACTAC279 4457 761 GAAATTGTGTTGACTCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGTACACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA 279 4458 762EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWYTFGQG TKVEIK 279 4459 763RASQSVSSYLA 279 4460 764 AGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCC 279 4461 765DASNRAT 279 4462 766 GATGCATCCAACAGGGCCACT 279 4463 767 QQRSNWYT 2794464 768 CAGCAGCGTAGCAACTGGTACACT 280 4465 769GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCCAGACTTCTGGTTACACCTTTAGTCATTTCGGTGTCACCTGGATACGACAGGCCCCAGGACAAGGGCTTGAGTGGCTGGGATGGATCAGCGCTTACAATGGTAACACAGACTATGCAGACAAACTGCAGGGCAGACTCACCATGACCACAGACACATCCACGAACACCGCCTACATGGAATTGAGGAGCCTCAGATCTGACGACACGGCCGTCTATTACTGTGCGAGAGATCCCCCCGCATCAGCTGCTGCGATGCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 280 4466 770EVQLVESGAEVKKPGASVKVSCQTSGYTFSHFGVTWIRQAPGQGLEWLGWISAYNGNTDYADKLQGRLTMTTDTSTNTAYMELRSLRSDDTAVYYCARDPPASAAAMLDYWGQGTLVTVSS 280 4467 771 YTFSHFGVT 280 4468 772TACACCTTTAGTCATTTCGGTGTCACC 280 4469 773 WISAYNGNTDYADKLQG 280 4470 774TGGATCAGCGCTTACAATGGTAACACAGACTATGCAGACAAACTGCA GGGC 280 4471 775ARDPPASAAAMLDY 280 4472 776 GCGAGAGATCCCCCCGCATCAGCTGCTGCGATGCTTGACTAC280 4473 777 GATATTGTGATGACTCAGTCTCCACTCTCCCTGGCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAAGTCTAGTCAAGGCCTCGAATACACTGATGGAAACACCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTCATTTATAAGATTTCTAACCGGGACTCTGGGGTTCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAGAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGTACACACGGGCGGGGAATCTCTTTCGGTCCTGGGACCAAAGTGGA TATCAAA 280 4474 778DIVMTQSPLSLAVTLGQPASISCKSSQGLEYTDGNTYLSWFQQRPGQSPRRLIYKISNRDSGVPDRFSGSGSGTDFTLRISRVEAEDVGVYYCMQGTHGR GISFGPGTKVDIK 2804475 779 KSSQGLEYTDGNTYLS 280 4476 780AAGTCTAGTCAAGGCCTCGAATACACTGATGGAAACACCTACTTGAG T 280 4477 781 KISNRDS280 4478 782 AAGATTTCTAACCGGGACTCT 280 4479 783 MQGTHGRGIS 280 4480 784ATGCAAGGTACACACGGGCGGGGAATCTCT 281 4481 785CAGGTGCAGCTGGTGCAGTCTGGGGCTGAAGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGACTACTTTATACACTGGGTGCGCCAGGCCCCTGGAGAAGGGCTTGAGTGGATGGGTTGGGTCAACCCTCTCAGTGACAACACAAAATATTCACAGAAGTTTCAGGGCAGGGTCACCATGAGCACGGACACGTCCATCACCACGGCCTACATGTACCTGAGCAGGCTGCGATTTGACGACACGGCCGTGTATTTTTGTGCGAGCCAATCTTCCCCCTATACCCCGGGCGCTCTGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 281 4482 786QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYFIHWVRQAPGEGLEWMGWVNPLSDNTKYSQKFQGRVTMSTDTSITTAYMYLSRLRFDDTAVYFCASQSSPYTPGALDVWGQGTTVTVSS 281 4483 787 YTFTDYFIH 281 4484 788TACACCTTCACCGACTACTTTATACAC 281 4485 789 WVNPLSDNTKYSQKFQG 281 4486 790TGGGTCAACCCTCTCAGTGACAACACAAAATATTCACAGAAGTTTCA GGGC 281 4487 791ASQSSPYTPGALDV 281 4488 792 GCGAGCCAATCTTCCCCCTATACCCCGGGCGCTCTGGACGTC281 4489 793 GACATCCAGTTGACCCAGTCTCCATCCTCCCTGCCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAACATTGGGAACAATTTAGCTTGGTATCAGCAGAAAGCAGGAAGAGCCCCCAAACTCCTGATCTATAGTGCGTCTAATTTCCATAGTGGGGTCCCATCAAGATTCATTGGCAGTGGATCTGGGACAGTTTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACCTACTTCTGTCAACAGAGTTTCACTCCCCAATTCACTTTCGGCCCTGGGACCAAGGTGGAAATCAAA 281 4490 794DIQLTQSPSSLPASVGDRVTITCRASQNIGNNLAWYQQKAGRAPKLLIYSASNFHSGVPSRFIGSGSGTVFTLTISSLQPEDFATYFCQQSFTPQFTFGPGT KVEIK 281 4491 795RASQNIGNNLA 281 4492 796 CGGGCAAGTCAGAACATTGGGAACAATTTAGCT 281 4493 797SASNFHS 281 4494 798 AGTGCGTCTAATTTCCATAGT 281 4495 799 QQSFTPQFT 2814496 800 CAACAGAGTTTCACTCCCCAATTCACT 282 4497 801CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAGGCCTGGGTCCTCGGTGAGGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGGAAGTATGCTATCAGTTGGGTGCGACAGGCCCGTGGACAAGGGCTTGAGTGGATGGGAGGCATCATCCCTATGTCCGGACCACCAAGCTACGCACAGAAGTTTCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGTCTACATGGAGCTGAGCAGCCTGAGATTTGAGGACACGGCCGTGTATTTCTGTGCGAGGGATATCGAGTGGTTCGTACTCATGGACCCTATCACATCCTACTACCCTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGT CTCCTCA 282 4498 802QVQLVQSGAEVKRPGSSVRVSCKASGGTFRKYAISWVRQARGQGLEWMGGIIPMSGPPSYAQKFQGRVTITADESTSTVYMELSSLRFEDTAVYFCARDIEWFVLMDPITSYYPMDVWGQGTTVTVSS 282 4499 803 GTFRKYAIS 282 4500 804GGCACCTTCAGGAAGTATGCTATCAGT 282 4501 805 GIIPMSGPPSYAQKFQG 282 4502 806GGCATCATCCCTATGTCCGGACCACCAAGCTACGCACAGAAGTTTCA GGGC 282 4503 807ARDIEWFVLMDPITSYYPMDV 282 4504 808GCGAGGGATATCGAGTGGTTCGTACTCATGGACCCTATCACATCCTAC TACCCTATGGACGTC 2824505 809 CAGTCTGTGGTGACCCAGGAGCCCTCACTGACTGTGTCCCCAGGAGGGACAGTCACTCTCACCTGTGGCTCCAGCACTGGAGGTGTCACCAGTGGTCATCATACATACTGGTTCCAGCAGAAGCCTGGCCAAGCCCCCAGGACACTGATCTATGATACGACCAACACACACTCCTGGACACCAGCCCGGTTCGCAGGCTCCCTCCTTGGGGGCAAAGCTGCCCTGACCCTTTCGGGTGCGCAGCCTGAGGATGAGGCTGACTATTACTGCCTCCTCTCCTATAGTGGTGCGCGGCCGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA 282 4506 810QSVVTQEPSLTVSPGGTVTLTCGSSTGGVTSGHHTYWFQQKPGQAPRTLIYDTTNTHSWTPARFAGSLLGGKAALTLSGAQPEDEADYYCLLSYSGARP VFGGGTKLTVL 282 4507811 GSSTGGVTSGHHTY 282 4508 812GGCTCCAGCACTGGAGGTGTCACCAGTGGTCATCATACATAC 282 4509 813 DTTNTHS 282 4510814 GATACGACCAACACACACTCC 282 4511 815 LLSYSGARPV 282 4512 816CTCCTCTCCTATAGTGGTGCGCGGCCGGTG 283 4513 817CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAATGATTACTACATGAATTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGGTTTCATACATTAGTAGTAGTGGTGAGACCAAATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGGAAATGAACAGCCTGAGAGTCGAGGACACGGCCGTCTACTACTGTGCGAGAGACGCGGTCATTGTAGTAGGACCGGTTGCTGTTCACTACCAATACTACGCGGACGTCTGGGGCAAAGGGACCACGGTCACCGTCT CTTCA 283 4514 818QVQLVQSGGGLVKPGGSLRLSCAASGFTFNDYYMNWIRQAPGKGLEWVSYISSSGETKYYADSVKGRFTISRDNAKNSLYLEMNSLRVEDTAVYYCARDAVIVVGPVAVHYQYYADVWGKGTTVTVSS 283 4515 819 FTFNDYYMN 283 4516 820TTCACCTTCAATGATTACTACATGAAT 283 4517 821 YISSSGETKYYADSVKG 283 4518 822TACATTAGTAGTAGTGGTGAGACCAAATACTACGCAGACTCTGTGAA GGGC 283 4519 823ARDAVIVVGPVAVHYQYYADV 283 4520 824GCGAGAGACGCGGTCATTGTAGTAGGACCGGTTGCTGTTCACTACCA ATACTACGCGGACGTC 2834521 825 CAGCCAGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGAAGCACCTCCAACATCGGAAGTAACACTGTACACTGGTACCAGCAACTCCCAGGAACGGCCCCCAGACTCCTCATCTATGTTATTAATCAGCGGCCCTCAGGGGTCCCAGACCGATTCTCCGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAATGGTCCGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 283 4522 826QPVLTQPPSASGTPGQRVTISCSGSTSNIGSNTVHWYQQLPGTAPRLLIYVINQRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGPVF GGGTKLTVL 283 4523827 SGSTSNIGSNTVH 283 4524 828 TCTGGAAGCACCTCCAACATCGGAAGTAACACTGTACAC283 4525 829 VINQRPS 283 4526 830 GTTATTAATCAGCGGCCCTCA 283 4527 831AAWDDSLNGPV 283 4528 832 GCAGCATGGGATGACAGCCTGAATGGTCCGGTG 284 4529 833CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCCTCTGGAGGCACCTTCAGCGGCTACCATATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTCGAGTGGATGGGAGGGATCATCCATCTATTTGGGACAGTTAACTACGCTCCGAAGTTCCAGGGCAGAGTCACGATCACCGCGGACGCATCCACGGGCACAGCCTACATGGAGTTAAACAGCCTGATGTCTGAAGACACGGCCGTTTATTATTGTGCGAGAGATGCCTACGAAGTGTGGACTGGTTCTTATCTCCCCCCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 284 4530 834QVQLVQSGAEVKKPGSSVKVSCKASGGTFSGYHISWVRQAPGQGLEWMGGIIHLFGTVNYAPKFQGRVTITADASTGTAYMELNSLMSEDTAVYYCARDAYEVWTGSYLPPFDYWGQGTLVTVSS 284 4531 835 GTFSGYHIS 284 4532 836GGCACCTTCAGCGGCTACCATATCAGC 284 4533 837 GIIHLFGTVNYAPKFQG 284 4534 838GGGATCATCCATCTATTTGGGACAGTTAACTACGCTCCGAAGTTCCAG GGC 284 4535 839ARDAYEVWTGSYLPPFDY 284 4536 840GCGAGAGATGCCTACGAAGTGTGGACTGGTTCTTATCTCCCCCCTTTT GACTAC 284 4537 841GAAATTGTGTTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCCGGGGAAAGAGTCACCCTCTCCTGCAGGGCCAGTCAGACTGTTACAAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATTCACCAGGGCCACTGACATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTCTGCAGTATATTATTGTCAGCAGTATGGTAGCTCATTCCTCACTTTCGGCGGAGGGACCAAAGTGGATATCAAA 284 4538 842EIVLTQSPGTLSLSPGERVTLSCRASQTVTSSYLAWYQQKPGQAPRLLIYGAFTRATDIPDRFSGSGSGTDFTLTISRLEPEDSAVYYCQQYGSSFLTFGGG TKVDIK 284 4539 843RASQTVTSSYLA 284 4540 844 AGGGCCAGTCAGACTGTTACAAGCAGCTACTTAGCC 284 4541845 GAFTRAT 284 4542 846 GGTGCATTCACCAGGGCCACT 284 4543 847 QQYGSSFLT284 4544 848 CAGCAGTATGGTAGCTCATTCCTCACT 285 4545 849GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGCAAAAGCCCGGGCGGTCCCTGCGACTCTCATGTTCAGCTTCTGGATTCACCTTTGGTGATTATGCTATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGGCCTGGAGTGGGTTGGTTTCATTAGAAGTAAAGCTTATGTTGGGACCGCAGAATACGCCGCGTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGCATCGCCTATCTGCACATGAACAGCCTGAAGACCGAGGACACAGCCGTGTATTACTGTACTAGAGATGATATTTTGACTGGTTTTTATGACCGCTCTTACTATTACGGTATACACGTCTGGGGCCAAGGGACCACGGTCACCGT CTCCTCA 285 4546 850EVQLVESGGGLQKPGRSLRLSCSASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYVGTAEYAASVKGRFTISRDDSKSIAYLHMNSLKTEDTAVYYCTRDDILTGFYDRSYYYGIHVWGQGTTVTVSS 285 4547 851 FTFGDYAMS 285 4548 852TTCACCTTTGGTGATTATGCTATGAGC 285 4549 853 FIRSKAYVGTAEYAASVKG 285 4550854 TTCATTAGAAGTAAAGCTTATGTTGGGACCGCAGAATACGCCGCGTCT GTGAAAGGC 285 4551855 TRDDILTGFYDRSYYYGIHV 285 4552 856ACTAGAGATGATATTTTGACTGGTTTTTATGACCGCTCTTACTATTAC GGTATACACGTC 285 4553857 GAAATTGTAATGACGCAGTCTCCAGTCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACAGCAACTTAGCCTGGTACCAGAAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAGTGCATCCACCAGGGCCACTGGTGTCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCGTCAGCAGCCTTCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATGATAACTGGCCTCCGTACACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA 285 4554 858EIVMTQSPVTLSVSPGERATLSCRASQSVNSNLAWYQKKPGQAPRLLIYSASTRATGVPARFSGSGSGTEFTLTVSSLQSEDFAVYYCQQYDNWPPYTF GQGTKVEIK 285 4555 859RASQSVNSNLA 285 4556 860 AGGGCCAGTCAGAGTGTTAACAGCAACTTAGCC 285 4557 861SASTRAT 285 4558 862 AGTGCATCCACCAGGGCCACT 285 4559 863 QQYDNWPPYT 2854560 864 CAGCAGTATGATAACTGGCCTCCGTACACT 286 4561 865CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAGGCCTTCACAGACCCTGTCCCTCACCTGCTCCGCCTCTGGTGCAGCCATCAATAGTGGTGATTATTACTGGAGTTGGATCCGCCAGGCCCCTGGGAGGGGCCTAGAGTGGATTGGGTCCATTTCCAACCGTGGGGTCACCGACTACAACCCGTCCCTCAAGAGTCGAGTTATCATATCAGCGGACACGTCCAAGAATCAGTTCTCCCTGAGGCTGACCTCTGTGACTGCCACAGACACGGCCGTGTATTATTGTGCCAGAGATTTGGGTACTTTGGCCTTTGATCCCTACTACTATTACGGTATTGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 286 4562 866QVQLQESGPGLVRPSQTLSLTCSASGAAINSGDYYWSWIRQAPGRGLEWIGSISNRGVTDYNPSLKSRVIISADTSKNQFSLRLTSVTATDTAVYYCARDLGTLAFDPYYYYGIDVWGQGTTVTVSS 286 4563 867 AAINSGDYYWS 286 4564 868GCAGCCATCAATAGTGGTGATTATTACTGGAGT 286 4565 869 SISNRGVTDYNPSLKS 286 4566870 TCCATTTCCAACCGTGGGGTCACCGACTACAACCCGTCCCTCAAGAGT 286 4567 871ARDLGTLAFDPYYYYGIDV 286 4568 872GCCAGAGATTTGGGTACTTTGGCCTTTGATCCCTACTACTATTACGGT ATTGACGTC 286 4569 873GACATCCGGATGACCCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGGCATTTAGCCTGGTACCAACAAAAACCTGGCCAGGCTCCCCGGCTCCTCATCTATGATGCATCATACAGGGTCACTGGCGTCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGGAGTCTGAAGATTTTGCAATTTATTTCTGTCAGCAGCGTAGCACCTGGCCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 286 4570 874DIRMTQSPATLSLSPGERATLSCRASQSVSRHLAWYQQKPGQAPRLLIYDASYRVTGVPDRFSGSGSGTDFTLTISSLESEDFAIYFCQQRSTWPTFGQGT KVEIK 286 4571 875RASQSVSRHLA 286 4572 876 AGGGCCAGTCAGAGTGTTAGCAGGCATTTAGCC 286 4573 877DASYRVT 286 4574 878 GATGCATCATACAGGGTCACT 286 4575 879 QQRSTWPT 2864576 880 CAGCAGCGTAGCACCTGGCCGACG 287 4577 881CAGGTGCAGCTGGTGGAATCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTGCCTGCACGGCGTCTGGATACGCCTTCACCAATTACAACATCCACTGGGTGCGACTGGCCCCTGGACAGGGACTTGAGTGGATGGCAATTATCAACCCCGGTAGTGGTGGCACAGACTACTCAGAGAAGTTCCAGGGCAGGCTCACCTTGACCAGTGACACGTCCACGAGCACGGTGTACATGACGCTGGGCAGCCTGAGATATGAAGACACGGCCTTTTATTACTGTGCGAGAAGGGGTTACCCTGATTCGGGGAGTTACCCCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 287 4578 882QVQLVESGAEVKKPGASVKVACTASGYAFTNYNIHWVRLAPGQGLEWMAIINPGSGGTDYSEKFQGRLTLTSDTSTSTVYMTLGSLRYEDTAFYYCARRGYPDSGSYPLDYWGQGTLVTVSS 287 4579 883 YAFTNYNIH 287 4580 884TACGCCTTCACCAATTACAACATCCAC 287 4581 885 IINPGSGGTDYSEKFQG 287 4582 886ATTATCAACCCCGGTAGTGGTGGCACAGACTACTCAGAGAAGTTCCA GGGC 287 4583 887ARRGYPDSGSYPLDY 287 4584 888GCGAGAAGGGGTTACCCTGATTCGGGGAGTTACCCCCTTGACTAC 287 4585 889GATATTGTGATGACGCAGTCTCCATCCTCCCTGTCTGCATCTCTGGGAGACAGAGTCACCATCACTTGCCGGGCAGGTCGGAGCATTGCCACTTACTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGGTGCATCCAGTTTGCAAAGTGGCGTCCCATCAAGGTTCAGTGGCAGTGGCTCTGGGACACATTTCACTCTCACCATCAGCAGTCTGCAACCTGAGGATTTTGCAACTTACTACTGTCAACAGAGTTACATCCGCCCTATCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA 287 4586 890DIVMTQSPSSLSASLGDRVTITCRAGRSIATYLNWYQQKPGKAPKLLIYGASSLQSGVPSRFSGSGSGTHFTLTISSLQPEDFATYYCQQSYIRPITFGGGT KVEIK 287 4587 891RAGRSIATYLN 287 4588 892 CGGGCAGGTCGGAGCATTGCCACTTACTTAAAT 287 4589 893GASSLQS 287 4590 894 GGTGCATCCAGTTTGCAAAGT 287 4591 895 QQSYIRPIT 2874592 896 CAACAGAGTTACATCCGCCCTATCACT 288 4593 897CAGGTGCAGCTGCAGGAGTCCGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTCGTCTCCTCAGCAGTGGTGATTACTACTGGAGTTGGATCCGCCAGTCCCCAGGGAGGGGCCTGGAGTGGATTGGCTACGTCTATCACAGTGGGACCACCTCGTACAACCCGTCCCTCAAGAGTCGAATTACCATGACAGTGGACACGTCCAAGAACCAGTTCAACCTGAGGTTGACCTCTGTAACGGCCGCAGACACGGCCGTGTATTACTGTGCCAGAGATCTCGGATATAGCAGTTCCTCTCCCGCCTTTTATTACGGTATAGACTTCTGGGGCCCAGGGACCATGGTCACCGTCTCTTCA 288 4594 898QVQLQESGPGLVKPSQTLSLTCTVSGRLLSSGDYYWSWIRQSPGRGLEWIGYVYHSGTTSYNPSLKSRITMTVDTSKNQFNLRLTSVTAADTAVYYCARDLGYSSSSPAFYYGIDFWGPGTMVTVSS 288 4595 899 RLLSSGDYYWS 288 4596 900CGTCTCCTCAGCAGTGGTGATTACTACTGGAGT 288 4597 901 YVYHSGTTSYNPSLKS 288 4598902 TACGTCTATCACAGTGGGACCACCTCGTACAACCCGTCCCTCAAGAGT 288 4599 903ARDLGYSSSSPAFYYGIDF 288 4600 904GCCAGAGATCTCGGATATAGCAGTTCCTCTCCCGCCTTTTATTACGGT ATAGACTTC 288 4601 905GAAATTGTATTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGCAAAGAGCGACCCTCTCCTGCAGGGCCAGTCAGAGTGTTGGCAACTACTTAGCCTGGTACCAACAAAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGTCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGGCTAGAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACGGGGTCCTCACTTTCGGCGGAGGGACCAAAGTGGATATCAAA 288 4602 906EIVLTQSPATLSLSPGQRATLSCRASQSVGNYLAWYQQKPGQAPRLLIYDASNRVTGIPARFSGSGSGTDFTLTISRLESEDFAVYYCQQRSNGVLTFGGG TKVDIK 288 4603 907RASQSVGNYLA 288 4604 908 AGGGCCAGTCAGAGTGTTGGCAACTACTTAGCC 288 4605 909DASNRVT 288 4606 910 GATGCATCCAACAGGGTCACT 288 4607 911 QQRSNGVLT 2884608 912 CAGCAGCGTAGCAACGGGGTCCTCACT 289 4609 913GAGGTGCAGCTGTTGGAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAGGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGACTACTTTATGAACTGGGTGCGACAGGCCCCTGGAGGGGGCCTTGAGTGGATGGGGTGGGTCAATCCTCTCAGTGGAGCCACAAAATATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCACGGACACGTCCATCACCACAGGGTACCTGGACTTGAGGAGCCTGAGAGTTGACGACACGGCCATCTATTTTTGTGCGAGCCAGTCTTCCCCTTACACCCCGGGCGCTATGGGCGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTTCA 289 4610 914EVQLLESGAEVKKPGASVRVSCKASGYTFTDYFMNWVRQAPGGGLEWMGWVNPLSGATKYAQKFQGRVTMTTDTSITTGYLDLRSLRVDDTAIYFCASQSSPYTPGAMGVWGQGTTVTVSS 289 4611 915 YTFTDYFMN 289 4612 916TACACCTTCACCGACTACTTTATGAAC 289 4613 917 WVNPLSGATKYAQKFQG 289 4614 918TGGGTCAATCCTCTCAGTGGAGCCACAAAATATGCACAGAAGTTTCA GGGC 289 4615 919ASQSSPYTPGAMGV 289 4616 920 GCGAGCCAGTCTTCCCCTTACACCCCGGGCGCTATGGGCGTC289 4617 921 GACATCCAGGTGACCCAGTCTCCATCCTCCCTGTCTGCCTCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCGGCTATTTAAGTTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATGCTACATCCAATTTATACAGTGGGGTCCCATCAAGGTTCAGTGGCCGTGATTCTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACTGAATTCCGGTGCCCTATTCACTTTCGGCCCTGGGACCAAGGTGGAGATCAAA 289 4618 922DIQVTQSPSSLSASVGDRVTITCRASQSISGYLSWYQQKPGKAPNLLIYATSNLYSGVPSRFSGRDSGTDFTLTITSLQPEDFATYFCQLNSGALFTFGPGT KVEIK 289 4619 923RASQSISGYLS 289 4620 924 CGGGCAAGTCAGAGCATTAGCGGCTATTTAAGT 289 4621 925ATSNLYS 289 4622 926 GCTACATCCAATTTATACAGT 289 4623 927 QLNSGALFT 2894624 928 CAACTGAATTCCGGTGCCCTATTCACT 290 4625 929CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTCCCTCCATCAGCGCTGGAGATTACAACTGGAATTGGATCCGCCAGGCCCCAGGGAAGGGCCTGGAGTGGGTTGGATACATCGATTACAGGGGCCTCACCCACTACAACCCGTCCCTCAAGGGTCGACTTTCCATATTAATGGACAGGTCGGCGAACCAGTTCTCCCTGGAGCTGAATTCTGTGACTGCCGCAGACACGGCCGTCTACTACTGTGCCAGGGACGTGGGGGTCTATAGTGGCTACGATGTCTTTCACTACTACGGCATGGACGTCTGGGGCCAGGGGACCACGGTCACCGTCT CCTCA 290 4626 930QVQLQESGPGLVKPSQTLSLTCTVSGPSISAGDYNWNWIRQAPGKGLEWVGYIDYRGLTHYNPSLKGRLSILMDRSANQFSLELNSVTAADTAVYYCARDVGVYSGYDVFHYYGMDVWGQGTTVTVSS 290 4627 931 PSISAGDYNWN 290 4628 932CCCTCCATCAGCGCTGGAGATTACAACTGGAAT 290 4629 933 YIDYRGLTHYNPSLKG 290 4630934 TACATCGATTACAGGGGCCTCACCCACTACAACCCGTCCCTCAAGGGT 290 4631 935ARDVGVYSGYDVFHYYGMDV 290 4632 936GCCAGGGACGTGGGGGTCTATAGTGGCTACGATGTCTTTCACTACTAC GGCATGGACGTC 290 4633937 GAAACGACACTCACGCAGTCTCCAGTCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGTATGTTAGGAACAACTACTTAGCCTGGTACCAACACAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAGTGCTTCCAGCAGGGTCACTGGCACCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGACTTTGCAGTGTATTACTGTCAGCAGTATGGTGGCTCACCTCCGGTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA 290 4634 938ETTLTQSPVTLSLSPGERATLSCRASQYVRNNYLAWYQHKPGQAPRLLIYSASSRVTGTPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGGSPPVTFG PGTKVDIK 290 4635939 RASQYVRNNYLA 290 4636 940 AGGGCCAGTCAGTATGTTAGGAACAACTACTTAGCC 2904637 941 SASSRVT 290 4638 942 AGTGCTTCCAGCAGGGTCACT 290 4639 943QQYGGSPPVT 290 4640 944 CAGCAGTATGGTGGCTCACCTCCGGTCACT 291 4641 945GAGGTGCAGCTGTTGGAGTCCGGGGGAGGCTTAGTTCAGCCTGGGGGGTCCCTGAGACTATCCTGTGCAGCCTCTGGATTCACCTTCAGTAATTACTGGATGCACTGGGTCCGCCAAGCTCCAGGGAAGGGGCTGGTGTGGGTCTCACGTATTAGCGGTGATGGAAGTGACACAACCTACGCGGACTCCGTGGAGGGCCGATTCACCATCTCCAGAGACAACGCCAGGAGTACACTGTATCTTCAACTGAATAGTCTCACAGGCGACGACACGGCTGTGTATTATTGTGCAAGAGATTTGTGGACCACCTCGCCCTACTTTGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 291 4642 946EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYWMHWVRQAPGKGLVWVSRISGDGSDTTYADSVEGRFTISRDNARSTLYLQLNSLTGDDTAVYYCARDLWTTSPYFDLWGQGTLVTVSS 291 4643 947 FTFSNYWMH 291 4644 948TTCACCTTCAGTAATTACTGGATGCAC 291 4645 949 RISGDGSDTTYADSVEG 291 4646 950CGTATTAGCGGTGATGGAAGTGACACAACCTACGCGGACTCCGTGGA GGGC 291 4647 951ARDLWTTSPYFDL 291 4648 952 GCAAGAGATTTGTGGACCACCTCGCCCTACTTTGACCTC 2914649 953 GAAATTGTATTGACACAGTCTCCTGGCACCCTGTCTGCATCTATTGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTCTTAATGGCTGGTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAGGCTCCTCATCTATAAGTCGTCTAGTTTAGAAAGCGGGGTCCCATCAAGGTTCAGCGGCAGTGCATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGACGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTGGGCGTTCGGCCAAGGGACCAAGGTGGACGTCAAA 291 4650 954EIVLTQSPGTLSASIGDRVTITCRASQSLNGWLAWYQQKPGKAPRLLIYKSSSLESGVPSRFSGSASGTEFTLTISSLQPDDFATYYCQQYNSWAFGQGTK VDVK 291 4651 955RASQSLNGWLA 291 4652 956 CGGGCCAGTCAGAGTCTTAATGGCTGGTTGGCC 291 4653 957KSSSLES 291 4654 958 AAGTCGTCTAGTTTAGAAAGC 291 4655 959 QQYNSWA 291 4656960 CAACAGTATAATAGTTGGGCG 292 4657 961CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTCCTGGAGCTGGATCCGCCAGTCCCCAGGGAAGGGGCTGGAGTGGATTGGAGAAATCAATCATAGAGGAAGCACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCGAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCTGTGTACTACTGTGCGGGGACCAATTATGGAGAGGTTAATACGAGTAACCAATACTTCTTCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTC A 292 4658 962QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYSWSWIRQSPGKGLEWIGEINHRGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAGTNYGEVNTSNQYFFGMDVWGQGTTVTVSS 292 4659 963 GSFSGYSWS 292 4660 964GGGTCCTTCAGTGGTTACTCCTGGAGC 292 4661 965 EINHRGSTNYNPSLKS 292 4662 966GAAATCAATCATAGAGGAAGCACCAACTACAACCCGTCCCTCAAGAG T 292 4663 967AGTNYGEVNTSNQYFFGMDV 292 4664 968GCGGGGACCAATTATGGAGAGGTTAATACGAGTAACCAATACTTCTT CGGTATGGACGTC 292 4665969 GACATCCGGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTACCACCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGCTGCATCCAATTTGGAAAGTGGGGTCCCATCAAGTTTCAGTGGCAGTGGATTTGGGACAGACTTCACTCTCACCATCAGCAGTCTGCAACCTGACGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTGCCCCGCTCACCTTCGGCGGAGGGACCAAAGTGGATATCAAA 292 4666 970DIRLTQSPSSLSASVGDRVTITCRASQSITTYLNWYQQKPGKAPKLLIYAASNLESGVPSSFSGSGFGTDFTLTISSLQPDDFATYYCQQSYSAPLTFGGGT KVDIK 292 4667 971RASQSITTYLN 292 4668 972 CGGGCAAGTCAGAGCATTACCACCTATTTAAAT 292 4669 973AASNLES 292 4670 974 GCTGCATCCAATTTGGAAAGT 292 4671 975 QQSYSAPLT 2924672 976 CAACAGAGTTACAGTGCCCCGCTCACC 293 4673 977CAGGTCCAGCTGGTACAGTCTGGGGCTGGGGTGAAGAAGCCTGGGGCCTCAGTGAGGGTCTCATGCACGGCCTCTGGATACACCTTCACCGACTACTTTATAAACTGGGTGCGACAGGCCCCTGGAGGGGGCCTTGAGTGGATGGGGTGGGTCAATCCTCTCAGTGGAGCCACAAGATACGCCCAGAACTTTGCGGGCAGGGTCACCATGACCACGGACACGTCCATCACCACAGGATATCTGGACTTACGGAACCTGCGACTTGACGACACGGCCGTCTATTTTTGTGCGAGCCAGTCTTCACCTTACACGCCGGGCGCTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 293 4674 978QVQLVQSGAGVKKPGASVRVSCTASGYTFTDYFINWVRQAPGGGLEWMGWVNPLSGATRYAQNFAGRVTMTTDTSITTGYLDLRNLRLDDTAVYFCASQSSPYTPGAMDVWGQGTTVTVSS 293 4675 979 YTFTDYFIN 293 4676 980TACACCTTCACCGACTACTTTATAAAC 293 4677 981 WVNPLSGATRYAQNFAG 293 4678 982TGGGTCAATCCTCTCAGTGGAGCCACAAGATACGCCCAGAACTTTGC GGGC 293 4679 983ASQSSPYTPGAMDV 293 4680 984 GCGAGCCAGTCTTCACCTTACACGCCGGGCGCTATGGACGTC293 4681 985 GATATTGTGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCTCCATCACTTGCCGGACAAGTCAGACCATTAGTGGCTATATAAGTTGGTATCAGAAGAAACCAGGAAAAGCCCCTAAACTCCTGATCTATGCTGCATCAAATATGTACAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGAATCTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACTGAATTCCGGTGCCCTATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA 293 4682 986DIVMTQSPSSLSASVGDRVSITCRTSQTISGYISWYQKKPGKAPKLLIYAASNMYSGVPSRFSGSESGTDFTLTITSLQPEDFATYFCQLNSGALFTFGPGT KVDIK 293 4683 987RTSQTISGYIS 293 4684 988 CGGACAAGTCAGACCATTAGTGGCTATATAAGT 293 4685 989AASNMYS 293 4686 990 GCTGCATCAAATATGTACAGT 293 4687 991 QLNSGALFT 2934688 992 CAACTGAATTCCGGTGCCCTATTCACT 294 4689 993GAGGTGCAGCTGGTGGAGTCTGCAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGTTTTGCCAGCCACTGGATCGGTTGGGTCCGCCAAATGCCCGGGAAAGGCCTGGAGTTGATGGGATTCATCTATCCTGGTGACTCTGATACCAGATACAACCCGTCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCAGCACCGCCTACCTGCAGTGGACCAGGCTGAAGGCCTCGGACACCGCCATGTACTACTGTGGCCAGGCAGTGGCGGGGGGTGAATATTTCCACCACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA 294 4690 994EVQLVESAAEVKKPGESLKISCKGSGYSFASHWIGWVRQMPGKGLELMGFIYPGDSDTRYNPSFQGQVTISADKSISTAYLQWTRLKASDTAMYYCG QAVAGGEYFHHWGQGTLVTVSS294 4691 995 YSFASHWIG 294 4692 996 TACAGTTTTGCCAGCCACTGGATCGGT 294 4693997 FIYPGDSDTRYNPSFQG 294 4694 998TTCATCTATCCTGGTGACTCTGATACCAGATACAACCCGTCCTTCCAA GGC 294 4695 999GQAVAGGEYFHH 294 4696 1000 GGCCAGGCAGTGGCGGGGGGTGAATATTTCCACCAC 294 46971001 GATATTGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTCTTGGCAGCGACTTAGCCTGGTACCAGCAGAAACCTGGCCAGACTCCCAGGCTCCTCATCTATGATGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCACTATAATAATTGGCCCCGGGGGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 294 4698 1002DIVMTQSPATLSVSPGERATLSCRASQSLGSDLAWYQQKPGQTPRLLIYDASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQHYNNWPRGFGQ GTKVEIK 294 4699 1003RASQSLGSDLA 294 4700 1004 AGGGCCAGTCAGAGTCTTGGCAGCGACTTAGCC 294 47011005 DASTRAT 294 4702 1006 GATGCATCCACCAGGGCCACT 294 4703 1007 QHYNNWPRG294 4704 1008 CAGCACTATAATAATTGGCCCCGGGGG 295 4705 1009CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACGGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGTCTCCGTCACCATTAATGATTACTACTGGACTTGGCTCCGCCAGTCCCCAGGGAAAGGCCTGGAGTGGATTGGAAACATCTATAACAGTGGGAGCACCTACCAGAACCCGTCCCTCCAGAGTCGAGTTACCATGTCAGTGGACACGGCCAAGAACCACTTCTCCCTGAAGCTGACCTCTGTCACTGCCGCAGATACGGCCGTCTATTACTGTGCCAGAGATTTAGGCACTGCCAACAACTACTACTTCGGTATGGACGTCTGGGGCCTAGGGACCACGGTCACCGTCTCCTCA 295 4706 1010QVQLQESGPGRVKPSQTLSLTCTVSGVSVTINDYYWTWLRQSPGKGLEWIGNIYNSGSTYQNPSLQSRVTMSVDTAKNHFSLKLTSVTAADTAVYYCARDLGTANNYYFGMDVWGLGTTVTVSS 295 4707 1011 VSVTINDYYWT 295 4708 1012GTCTCCGTCACCATTAATGATTACTACTGGACT 295 4709 1013 NIYNSGSTYQNPSLQS 2954710 1014 AACATCTATAACAGTGGGAGCACCTACCAGAACCCGTCCCTCCAGAG T 295 47111015 ARDLGTANNYYFGMDV 295 4712 1016GCCAGAGATTTAGGCACTGCCAACAACTACTACTTCGGTATGGACGT C 295 4713 1017GAAATTGTGATGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACTCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCACCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAATGGATCCAACAGGGTCACTGGCACCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCGTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCCGTACACTTTTGGCCAGGGGACCAAGGTGGAGATCAAA 295 4714 1018EIVMTQSPATLSLSPGERATLSCRASQSVSTYLAWYQQKPGQAPRLLIYNGSNRVTGTPARFSGSGSGTDFTLTISSVEPEDFAVYYCQQRSNWPPYTFG QGTKVEIK 295 47151019 RASQSVSTYLA 295 4716 1020 AGGGCCAGTCAGAGTGTTAGCACCTACTTAGCC 2954717 1021 NGSNRVT 295 4718 1022 AATGGATCCAACAGGGTCACT 295 4719 1023QQRSNWPPYT 295 4720 1024 CAGCAGCGTAGCAACTGGCCTCCGTACACT 296 4721 1025CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCTCGGTCTCTGGTGCCTCCGTCACCAGTAGGGAATACTACTGGGGCTGGATCCGCCAGGCCCCCGGGAAGGGTCTGCAGTGGATTGCCAGCATTCATCACAGTCCTTTTCAAAGTGACGGCAACCCGTCCCTGACGAGTCGCGTCTCCAGTTCCGTAGTCACGTCCAAGAACCAGTTGGCCCTGAGGCTGAGCTCTGTGACCGCCGCAGACACGGCTGTATATTACTGTGCGGGCGCGTTTTGGGAGGTTTGGACTGGCCTTTATTCACCGCCGTTTGACTTTTGGGGCCAGGGAATCCTGGTCACCGTCTCCTCA 296 4722 1026QVQLQESGPGLVKPSETLSLTCSVSGASVTSREYYWGWIRQAPGKGLQWIASIHHSPFQSDGNPSLTSRVSSSVVTSKNQLALRLSSVTAADTAVYYCAGAFWEVWTGLYSPPFDFWGQGILVTVSS 296 4723 1027 ASVTSREYYWG 296 4724 1028GCCTCCGTCACCAGTAGGGAATACTACTGGGGC 296 4725 1029 SIHHSPFQSDGNPSLTS 2964726 1030 AGCATTCATCACAGTCCTTTTCAAAGTGACGGCAACCCGTCCCTGACG AGT 296 47271031 AGAFWEVWTGLYSPPFDF 296 4728 1032GCGGGCGCGTTTTGGGAGGTTTGGACTGGCCTTTATTCACCGCCGTTT GACTTT 296 4729 1033GAAATTGTAATGACACAGTCTCCAGGGACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCTGGGCCAGTCAGACTGTTAGCAGCGGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCTACCAGGGCCACTGACATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGGCTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATCTTGCAGTCTATTACTGTCAGCAGTATAGCAGTTCACCACTCACTTTCGGCGGCGGGACCAAGGTGGAAATCAAA 296 4730 1034EIVMTQSPGTLSLSPGERATLSCWASQTVSSGYLAWYQQKPGQAPRLLIYGASTRATDIPDRFSGSGSGTGFTLTISRLEPEDLAVYYCQQYSSSPLTFGG GTKVEIK 296 47311035 WASQTVSSGYLA 296 4732 1036 TGGGCCAGTCAGACTGTTAGCAGCGGCTACTTAGCC 2964733 1037 GASTRAT 296 4734 1038 GGTGCATCTACCAGGGCCACT 296 4735 1039QQYSSSPLT 296 4736 1040 CAGCAGTATAGCAGTTCACCACTCACT 297 4737 1041CAGGTGCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCGTGCAAGACTTCTGGTTACACCTTTTCCAACTACGGTATCAGCTGGCTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGCATGGATCAGCCCTTATAATGGGAACACAAAGTCTGCACAGAGGTTTCAGGGCAGAGTCATCATGACCACAGACACATCCACGAGGACAGCCCACATGGAGGTGAAGAGCCTGAGAACTGACGACACGGCCACATATTACTGTGCGAGAGATCCAGCAGTCGATGCAATACCGATGCTTGACTACTGGGGCCAGGGAACCACGGTCACCGTCTCCTCA 297 4738 1042QVQLVQSGAEVKKPGASVKVSCKTSGYTFSNYGISWLRQAPGQGLEWMAWISPYNGNTKSAQRFQGRVIMTTDTSTRTAHMEVKSLRTDDTATYYCARDPAVDAIPMLDYWGQGTTVTVSS 297 4739 1043 YTFSNYGIS 297 4740 1044TACACCTTTTCCAACTACGGTATCAGC 297 4741 1045 WISPYNGNTKSAQRFQG 297 47421046 TGGATCAGCCCTTATAATGGGAACACAAAGTCTGCACAGAGGTTTCA GGGC 297 4743 1047ARDPAVDAIPMLDY 297 4744 1048 GCGAGAGATCCAGCAGTCGATGCAATACCGATGCTTGACTAC297 4745 1049 GACATCCAGGTGACCCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTGTACACTGATGGAAACACCTACTTGAGCTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAGGGTTTCTCACCGGGACTCTGGGGTCCCAGACAGATTCACCGGCAGTGGGTCAGGCACTGATTTCACACTGATAATCCGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGTACACACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAAAT CAAA 297 4746 1050DIQVTQSPLSLPVTLGQPASISCRSSQSLVYTDGNTYLSWFQQRPGQSPRRLIYRVSHRDSGVPDRFTGSGSGTDFTLIIRRVEAEDVGVYYCMQGTHWPL TFGGGTKVEIK 297 47471051 RSSQSLVYTDGNTYLS 297 4748 1052AGGTCTAGTCAAAGCCTCGTGTACACTGATGGAAACACCTACTTGAG C 297 4749 1053 RVSHRDS297 4750 1054 AGGGTTTCTCACCGGGACTCT 297 4751 1055 MQGTHWPLT 297 47521056 ATGCAAGGTACACACTGGCCTCTCACT 298 4753 1057CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACGTTCAGTGACTATGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAATCATATCATATGATGCAAATAATAAATATTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGACCTGAGGACACGGCTGTATATTACTGTGCGAAAGAAGAGTGGCTGGTGCCAGCCTACTGGGGCCAGGGAA TCCTGGTCACCGTCTCCTCA 2984754 1058 QVQLVQSGGGVVQPGRSLRLSCAASGFTFSDYAMHWVRQAPGKGLEWVAIISYDANNKYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYC AKEEWLVPAYWGQGILVTVSS298 4755 1059 FTFSDYAMH 298 4756 1060 TTCACGTTCAGTGACTATGCCATGCAC 2984757 1061 IISYDANNKYYADSVKG 298 4758 1062ATCATATCATATGATGCAAATAATAAATATTATGCAGACTCCGTGAA GGGC 298 4759 1063AKEEWLVPAY 298 4760 1064 GCGAAAGAAGAGTGGCTGGTGCCAGCCTAC 298 4761 1065CAGTCTGTGCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGATATAATTACGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCTTAATTTATGAGGTCTCTAATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGCCTGAGGACGAGGCTGATTATTACTGCAGCTCATATTCAACCAATAGTGCCCCCTTTGGAACTGGGACCAAGCTCACCGTCCTA 298 4762 1066QSVLTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLLIYEVSNRPSGVSNRFSGSKSGNTASLTISGLQPEDEADYYCSSYSTNSAPFG TGTKLTVL 298 47631067 TGTSSDVGGYNYVS 298 4764 1068ACTGGAACCAGCAGTGACGTTGGTGGATATAATTACGTCTCC 298 4765 1069 EVSNRPS 2984766 1070 GAGGTCTCTAATCGGCCCTCA 298 4767 1071 SSYSTNSAP 298 4768 1072AGCTCATATTCAACCAATAGTGCCCCC 299 4769 1073CAGGTCCAGCTTGTGCAGTCTGGGGGAGGCGTGGTCCAGTCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTGACAATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGGAATCTTTCATGATGGGAGTAATAAACAATATGCAGAATCCGTGAAGGGCCGATTCATCATCTCCAGAGACAATTCCAAGAACACTCTCTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTCTATATTTCTGTGCGAGAGCCCCTTACGATATTTGGAGCGGATATTGTCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 299 4770 1074QVQLVQSGGGVVQSGRSLRLSCAASGFTFSDNGMHWVRQAPGKGLEWVAGIFHDGSNKQYAESVKGRFIISRDNSKNTLYLQMNSLRAEDTALYFCARAPYDIWSGYCLDYWGQGTLVTVSS 299 4771 1075 FTFSDNGMH 299 4772 1076TTCACCTTCAGTGACAATGGCATGCAC 299 4773 1077 GIFHDGSNKQYAESVKG 299 47741078 GGAATCTTTCATGATGGGAGTAATAAACAATATGCAGAATCCGTGAA GGGC 299 4775 1079ARAPYDIWSGYCLDY 299 4776 1080GCGAGAGCCCCTTACGATATTTGGAGCGGATATTGTCTTGACTAC 299 4777 1081GACATCCGGATGACCCAGTCTCCAGCCACCCTGTCTCTGTCTCCAGGGGAAAGCGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTATCAACAACTTAGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCTACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGAGACAGAGTTCACTCTCACTATCAGCAGCCTGCAGTCTGAAGATTTCGCGGTTTATCACTGTCAGCAGTATAGTATCTGGCCTCAGACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 299 4778 1082DIRMTQSPATLSLSPGESATLSCRASQSVINNLAWYQQRPGQAPRLLIYGASTRATGIPARFSGSGSETEFTLTISSLQSEDFAVYHCQQYSIWPQTFGQG TKLEIK 299 4779 1083RASQSVINNLA 299 4780 1084 AGGGCCAGTCAGAGTGTTATCAACAACTTAGCC 299 47811085 GASTRAT 299 4782 1086 GGTGCATCTACCAGGGCCACT 299 4783 1087 QQYSIWPQT299 4784 1088 CAGCAGTATAGTATCTGGCCTCAGACT 300 4785 1089GAGGTGCAGCTGTTGGAGTCCGGGGGAGGCGTGGTCCAGTCTGGGAGGTCCCTGAGACTCTCCTGTGTAGCGTCTGGATTCACCTTCAGTGACAGTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGGTTTATTTTATGATGGAAGTAATAAACAATATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAGCACACTGTATCTGCAGATGAACAGCCTGAGGGCCGAGGACACGGCTGTTTATTACTGTGCGAGAGCCCCTTACGATATTTGGAGTGGTTATTGTCTTGACTACTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA 300 4786 1090EVQLLESGGGVVQSGRSLRLSCVASGFTFSDSGMHWVRQAPGKGLEWVAGLFYDGSNKQYADSVKGRFTISRDNSKSTLYLQMNSLRAEDTAVYYCARAPYDIWSGYCLDYWGQGTLVTVSS 300 4787 1091 FTFSDSGMH 300 4788 1092TTCACCTTCAGTGACAGTGGCATGCAC 300 4789 1093 GLFYDGSNKQYADSVKG 300 47901094 GGTTTATTTTATGATGGAAGTAATAAACAATATGCAGACTCCGTGAA GGGC 300 4791 1095ARAPYDIWSGYCLDY 300 4792 1096GCGAGAGCCCCTTACGATATTTGGAGTGGTTATTGTCTTGACTAC 300 4793 1097GAAATTGTATTGACACAGTCTCCAGCCACCCTGTATATGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACAACAACTTAGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCTACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGAGACAGAGTTCACTCTCACTATCAGCAGCCTGCAGTCTGAAGATTTTGCGGTTTATCACTGTCAGCAGTATAGTATCTGGCCTCAGACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 300 4794 1098EIVLTQSPATLYMSPGERATLSCRASQSVNNNLAWYQQRPGQAPRLLIYGASTRATGIPARFSGSGSETEFTLTISSLQSEDFAVYHCQQYSIWPQTFGQ GTKLEIK 300 47951099 RASQSVNNNLA 300 4796 1100 AGGGCCAGTCAGAGTGTTAACAACAACTTAGCC 3004797 1101 GASTRAT 300 4798 1102 GGTGCATCTACCAGGGCCACT 300 4799 1103QQYSIWPQT 300 4800 1104 CAGCAGTATAGTATCTGGCCTCAGACT 301 4801 1105CAGGTCCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCGTGCAAGACTTCTGGTTACACCTTTTCCAACTACGGTATCAGCTGGCTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGCATGGATCAGCCCTTATAATGGGAACACAAAGTCTGCACAGAGGTTTCAGGGCAGAGTCATCATGACCACAGACACATCCACGAGGACAGCCCACATGGAGGTGAAGAGCCTGAGAACTGACGACACGGCCACATATTACTGTGCGAGAGATCCAGCAGTCGATGCAATACCGATGCTTGACTACTGGGGCCAGGGAACCATGGTCACCGTCTCCTCA 301 4802 1106QVQLVQSGAEVKKPGASVKVSCKTSGYTFSNYGISWLRQAPGQGLEWMAWISPYNGNTKSAQRFQGRVIMTTDTSTRTAHMEVKSLRTDDTATYYCARDPAVDAIPMLDYWGQGTMVTVSS 301 4803 1107 YTFSNYGIS 301 4804 1108TACACCTTTTCCAACTACGGTATCAGC 301 4805 1109 WISPYNGNTKSAQRFQG 301 48061110 TGGATCAGCCCTTATAATGGGAACACAAAGTCTGCACAGAGGTTTCA GGGC 301 4807 1111ARDPAVDAIPMLDY 301 4808 1112 GCGAGAGATCCAGCAGTCGATGCAATACCGATGCTTGACTAC301 4809 1113 GAAATTGTGTTGACACAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTGTACACTGATGGAAACACCTACTTGAGCTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAGGGTTTCTCACCGGGACTCTGGGGTCCCAGACAGATTCACCGGCAGTGGGTCAGGCACTGATTTCACACTGATAATCCGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGTACACACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAAAT CAAA 301 4810 1114EIVLTQSPLSLPVTLGQPASISCRSSQSLVYTDGNTYLSWFQQRPGQSPRRLIYRVSHRDSGVPDRFTGSGSGTDFTLIIRRVEAEDVGVYYCMQGTHWPL TFGGGTKVEIK 301 48111115 RSSQSLVYTDGNTYLS 301 4812 1116AGGTCTAGTCAAAGCCTCGTGTACACTGATGGAAACACCTACTTGAG C 301 4813 1117 RVSHRDS301 4814 1118 AGGGTTTCTCACCGGGACTCT 301 4815 1119 MQGTHWPLT 301 48161120 ATGCAAGGTACACACTGGCCTCTCACT 302 4817 1121GAGGTGCAGCTGGTGGAGTCGGGCCCAAGACTGGTGAGGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGAGGCTTCATCAAAACTAGTAGTTACTACTGGGGCTGGATCCGTCAGCCCCCAGGGAAGGGGCTAGAGTGGATTGGGAGTATCTATTATGCTGGGACCACCTACTACAACCCGTCCCTCCAGAGTCGAGTCACCATGTCCGTTGACACGTCGAACAACCAGTTCTCCCTGAAGCTGAACTCTGTGACCGCCGCAGACACGGCTGTATATTACTGTGCGACCGCCTGGACTTTTGACCACTGGGGCCAGGGAACCCT GGTCACTGTCTCCTCA 3024818 1122 EVQLVESGPRLVRPSETLSLTCTVSGGFIKTSSYYWGWIRQPPGKGLEWIGSIYYAGTTYYNPSLQSRVTMSVDTSNNQFSLKLNSVTAADTAVYYCAT AWTFDHWGQGTLVTVSS 3024819 1123 GFIKTSSYYWG 302 4820 1124 GGCTTCATCAAAACTAGTAGTTACTACTGGGGC302 4821 1125 SIYYAGTTYYNPSLQS 302 4822 1126AGTATCTATTATGCTGGGACCACCTACTACAACCCGTCCCTCCAGAGT 302 4823 1127 ATAWTFDH302 4824 1128 GCGACCGCCTGGACTTTTGACCAC 302 4825 1129GAAATTGTATTGACACAGTCTCCAGCCACCCTGTCCTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTCTTAGCAACTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCTGCGTGGCCACTGGCCCCCCACGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA 302 4826 1130EIVLTQSPATLSLSPGERATLSCRASQSLSNYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQLRGHWPPTITFG QGTRLEIK 302 48271131 RASQSLSNYLA 302 4828 1132 AGGGCCAGTCAGAGTCTTAGCAACTACTTAGCC 3024829 1133 DASNRAT 302 4830 1134 GATGCATCCAACAGGGCCACT 302 4831 1135QLRGHWPPTIT 302 4832 1136 CAGCTGCGTGGCCACTGGCCCCCCACGATCACC 303 48331137 CAGGTCCAGCTTGTACAGTCTGGGGGAGGCTTGGTTCAGCCGGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCGCCTTTAGCGACTATACCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAAGTGTTAGTGGCACGGGTGGTACCTCATACTACGCAGACTCCGTGAATGGCCGGTTCGCCATCTCCAGAGAGAATTCCAAGAACACGCTGTTTCTGCAAATGGACAGCCTGAGAGCCGAGGACACGGCCACTTACTACTGTGCCAAAGATGGGTTGAGGGACGTATCGAGGGTTTATTACATCGACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCA 303 4834 1138QVQLVQSGGGLVQPGGSLRLSCAASGFAFSDYTMSWVRQAPGKGLEWVSSVSGTGGTSYYADSVNGRFAISRENSKNTLFLQMDSLRAEDTATYYCAKDGLRDVSRVYYIDVWGKGTTVTVSS 303 4835 1139 FAFSDYTMS 303 4836 1140TTCGCCTTTAGCGACTATACCATGAGC 303 4837 1141 SVSGTGGTSYYADSVNG 303 48381142 AGTGTTAGTGGCACGGGTGGTACCTCATACTACGCAGACTCCGTGAA TGGC 303 4839 1143AKDGLRDVSRVYYIDV 303 4840 1144GCCAAAGATGGGTTGAGGGACGTATCGAGGGTTTATTACATCGACGT C 303 4841 1145CAGCCTGTGCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCCGTGACATTGGTTCTCATGACTCTGTCTCCTGGTACCAACAAAAGCCAGGCAAAGCCCCCAAACTCATCATTTATGCAGTCAGAAATCGGCCCTCAGGGCTTTCTAATCGCTTCTCTGGTTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGACTGAAGACGAAGGTGACTATTACTGCAGCTCATATAGAAACGGCAACGCTCTGGGGGTCTTCGGAACTGGGACCAAGGTCACCGTCCTC 303 4842 1146QPVLTQPASVSGSPGQSITISCTGTSRDIGSHDSVSWYQQKPGKAPKLIIYAVRNRPSGLSNRFSGSKSGNTASLTISGLQTEDEGDYYCSSYRNGNALGV FGTGTKVTVL 303 48431147 TGTSRDIGSHDSVS 303 4844 1148ACTGGAACCAGCCGTGACATTGGTTCTCATGACTCTGTCTCC 303 4845 1149 AVRNRPS 3034846 1150 GCAGTCAGAAATCGGCCCTCA 303 4847 1151 SSYRNGNALGV 303 4848 1152AGCTCATATAGAAACGGCAACGCTCTGGGGGTC 304 4849 1153CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTTCAGCCGGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCGCCTTTAGCAACTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAAGTGTTAGTGGCACGGGTGGTACCACATACTACGCAGACTCCGTGAACGGGCGGTTCGCCATCTCCAGAGAGAATTCCAGGAACACCCTCTATCTGCAAATGGATAGCCTGAGAGTCGAGGACACGGCCACTTATTACTGTGCCAAAGATGGGTTGAGGGACTTATCGAGGGTCTATTACATCGACGTCTGGGGCAAAGGGGCCACGGTCACCGTCTCTTCA 304 4850 1154QVQLVESGGGLVQPGGSLRLSCAASGFAFSNYAMSWVRQAPGKGLEWVSSVSGTGGTTYYADSVNGRFAISRENSRNTLYLQMDSLRVEDTATYYCAKDGLRDLSRVYYIDVWGKGATVTVSS 304 4851 1155 FAFSNYAMS 304 4852 1156TTCGCCTTTAGCAACTATGCCATGAGC 304 4853 1157 SVSGTGGTTYYADSVNG 304 48541158 AGTGTTAGTGGCACGGGTGGTACCACATACTACGCAGACTCCGTGAA CGGG 304 4855 1159AKDGLRDLSRVYYIDV 304 4856 1160GCCAAAGATGGGTTGAGGGACTTATCGAGGGTCTATTACATCGACGT C 304 4857 1161CAGTCTGTCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCCGTGACATTGGTAGTCATGACTATGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCATCATTTATGGGGTCAATAATCGGCCCTCAGGACTTTCTAATCGCTTCTCTGGTTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGACTGAAGACGAAGGTGACTATTACTGCAGCTCATATAGAAACGGCAACACTCTGGGGGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA 304 4858 1162QSVLTQPASVSGSPGQSITISCTGTSRDIGSHDYVSWYQQHPGKAPKLIIYGVNNRPSGLSNRFSGSKSGNTASLTISGLQTEDEGDYYCSSYRNGNTLGV FGTGTKLTVL 304 48591163 TGTSRDIGSHDYVS 304 4860 1164ACTGGAACCAGCCGTGACATTGGTAGTCATGACTATGTCTCC 304 4861 1165 GVNNRPS 3044862 1166 GGGGTCAATAATCGGCCCTCA 304 4863 1167 SSYRNGNTLGV 304 4864 1168AGCTCATATAGAAACGGCAACACTCTGGGGGTC 305 4865 1169CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCCTCTGGAGGCACCTTCAGCGGCTACGCTATCAACTGGGTGCGACAGGCCCCTGGACAAGGGCTCGAGTGGATGGGAGGGATCATCCATATATTTGGGACAGTAAACTACGCTCCGAAGTTCCAGGGCAGACTCACGATAACCGCGGACGCATCCACGGGCACAGCCTACATGGAATTGAGCAGCCTGATGTCTGAGGACACGGCCCTATATTATTGTGCGAGAGATGCTTACGAAGTGTGGACCGGTTCTTATCTCCCCCCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 305 4866 1170QVQLVQSGAEVKKPGSSVKVSCKASGGTFSGYAINWVRQAPGQGLEWMGGIIHIFGTVNYAPKFQGRLTITADASTGTAYMELSSLMSEDTALYYCARDAYEVWTGSYLPPFDYWGQGTLVTVSS 305 4867 1171 GTFSGYAIN 305 4868 1172GGCACCTTCAGCGGCTACGCTATCAAC 305 4869 1173 GIIHIFGTVNYAPKFQG 305 48701174 GGGATCATCCATATATTTGGGACAGTAAACTACGCTCCGAAGTTCCA GGGC 305 4871 1175ARDAYEVWTGSYLPPFDY 305 4872 1176GCGAGAGATGCTTACGAAGTGTGGACCGGTTCTTATCTCCCCCCTTTT GACTAC 305 4873 1177GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCCGGGGAAAGAGTCACCCTCTCCTGCAGGGCCAGTCAGACTGTTACAAGCAACTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATTCACCAGGGCCACTGGCGTCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTTTACTATTGTCAGCAGTATGGTAGCTCATTCCTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA 305 4874 1178ETTLTQSPGTLSLSPGERVTLSCRASQTVTSNYLAWYQQKPGQAPRLLIYDAFTRATGVPARFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSFLTFGG GTKVEIK 305 48751179 RASQTVTSNYLA 305 4876 1180 AGGGCCAGTCAGACTGTTACAAGCAACTACTTAGCC 3054877 1181 DAFTRAT 305 4878 1182 GATGCATTCACCAGGGCCACT 305 4879 1183QQYGSSFLT 305 4880 1184 CAGCAGTATGGTAGCTCATTCCTCACT 306 4881 1185GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGTCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCATCTTCAGTGACAATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGGTATTTTTTATGATGGAAGTAATAAACAATATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACACTGTATCTGCAAATGAAGAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGCCCCTTACGATATCTGGAGTGGTTATTGTCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 306 4882 1186EVQLVESGGGVVQSGRSLRLSCAASGFIFSDNGMHWVRQAPGKGLEWVAGIFYDGSNKQYADSVKGRFTISRDNSKNTLYLQMKSLRAEDTAVYYCARAPYDIWSGYCLDYWGQGTLVTVSS 306 4883 1187 FIFSDNGMH 306 4884 1188TTCATCTTCAGTGACAATGGCATGCAC 306 4885 1189 GIFYDGSNKQYADSVKG 306 48861190 GGTATTTTTTATGATGGAAGTAATAAACAATATGCAGACTCCGTGAA GGGC 306 4887 1191ARAPYDIWSGYCLDY 306 4888 1192GCGAGAGCCCCTTACGATATCTGGAGTGGTTATTGTCTTGACTAC 306 4889 1193GACATCCAGGTGACCCAGTCTCCAGCCACCCTGTCTATGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACAACAACTTAGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCTACGAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGAGACAGAGTTCACTCTCACTATCAGCAGCCTGCAGTCTGAAGATTTTGCGGTTTATCACTGTCAGCAGTATAGTATCTGGCCTCAGACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA 306 4890 1194DIQVTQSPATLSMSPGERATLSCRASQSVNNNLAWYQQRPGQAPRLLIYGASTRATGIPARFSGSGSETEFTLTISSLQSEDFAVYHCQQYSIWPQTFGQ GTKVEIK 306 48911195 RASQSVNNNLA 306 4892 1196 AGGGCCAGTCAGAGTGTTAACAACAACTTAGCC 3064893 1197 GASTRAT 306 4894 1198 GGTGCATCTACGAGGGCCACT 306 4895 1199QQYSIWPQT 306 4896 1200 CAGCAGTATAGTATCTGGCCTCAGACT 307 4897 1201CAGGTCCAGCTTGTACAGTCTGGGGCTGAACTAAAGAAGCCTGGCTCCTCGGTGAAAGTCTCCTGCAAGGCTTCTGCAGACACCTTCAAAAGTTATGCTATCAACTGGGTGCGGCAGGCCCCTGGACAAGGACTTGAGTGGATGGGAGAGTTCATCCCAATCTTTGGTGTCTCACCCTCCGCACAGAAGTTCCAGGGCAGAGTCACCATTACCGCGGACAGATCCACGTCCACAGCCTACATGGAGTTGAGCAGCCTGAAATCTGATGACTCGGCCATTTATTACTGTGCGACACGTCTGTATACGTTGGGGTCCCCTTTTGACAATTGGGGCCAGGGGACCACGGTCACCGTCTCCTCA 307 4898 1202QVQLVQSGAELKKPGSSVKVSCKASADTFKSYAINWVRQAPGQGLEWMGEFIPIFGVSPSAQKFQGRVTITADRSTSTAYMELSSLKSDDSAIYYCATRLYTLGSPFDNWGQGTTVTVSS 307 4899 1203 DTFKSYAIN 307 4900 1204GACACCTTCAAAAGTTATGCTATCAAC 307 4901 1205 EFIPIFGVSPSAQKFQG 307 49021206 GAGTTCATCCCAATCTTTGGTGTCTCACCCTCCGCACAGAAGTTCCAG GGC 307 4903 1207ATRLYTLGSPFDN 307 4904 1208 GCGACACGTCTGTATACGTTGGGGTCCCCTTTTGACAAT 3074905 1209 CAGCCTGTGCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGTAGTGATGTTGGTGATTATGACTATGTCTCCTGGTACCAACACCTCCCAGGCGAAGTCCCCAAACTCATAGTTTATAATGTCATTAAGCGGCCCTCTGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGAGGATGAGGCTGACTATTACTGCTGCTCATATGCAGGCAGGTATATTTATGTCTTCGGCAGTGGGACCAAGCTCACCGTCCTA 307 4906 1210QPVLTQPRSVSGSPGQSVTISCTGTSSDVGDYDYVSWYQHLPGEVPKLIVYNVIKRPSGVPDRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGRYIYV FGSGTKLTVL 307 49071211 TGTSSDVGDYDYVS 307 4908 1212ACTGGAACCAGTAGTGATGTTGGTGATTATGACTATGTCTCC 307 4909 1213 NVIKRPS 3074910 1214 AATGTCATTAAGCGGCCCTCT 307 4911 1215 CSYAGRYIYV 307 4912 1216TGCTCATATGCAGGCAGGTATATTTATGTC 308 4913 1217GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGAGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCCTTAGTGGCTACTACATGAATTGGGTCCGCCAGGCTCCAGGGAGGGGGCTGGAGTGGGTCTCCTCCATTAGTGGTGGTAGTAATTACATAAACTACGCCGACTCAGTGAAGGGCCGGTTCACCATCTCCAGAGACAACGCCAAGAACTCACTCTATCTGCAAATGAACAGCCTGAGAGTCGAGGACACGGCTGTCTATTACTGTGCGAGGGTCCACGTGGATTTAGTGACTACGATTTTTGGGGTTGACTTTGACTTCTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA 308 4914 1218EVQLLESGGGLVKPGESLRLSCAASGFTLSGYYMNWVRQAPGRGLEWVSSISGGSNYINYADSVKGRFTISRDNAKNSLYLQMNSLRVEDTAVYYCARVHVDLVTTIFGVDFDFWGQGTLVTVSS 308 4915 1219 FTLSGYYMN 308 4916 1220TTCACCCTTAGTGGCTACTACATGAAT 308 4917 1221 SISGGSNYINYADSVKG 308 49181222 TCCATTAGTGGTGGTAGTAATTACATAAACTACGCCGACTCAGTGAA GGGC 308 4919 1223ARVHVDLVTTIFGVDFDF 308 4920 1224GCGAGGGTCCACGTGGATTTAGTGACTACGATTTTTGGGGTTGACTTT GACTTC 308 4921 1225CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGGTATGATGTACACTGGTACCAGCAACTTCCAGGAACAGCCCCCAAACTCCTCATCTATGGTAACACCAATCGGCCCGCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCTCCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCGTATGACAGCAGCCTGAGTGGTGCGATCTTCGGCGGAGGGACCAAGCTCACCGTCC TA 308 4922 1226QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNTNRPAGVPDRFSGSKSGSSASLAITGLQAEDEADYYCQSYDSSLSGA IFGGGTKLTVL 308 49231227 TGSSSNIGAGYDVH 308 4924 1228ACTGGGAGCAGCTCCAACATCGGGGCAGGGTATGATGTACAC 308 4925 1229 GNTNRPA 3084926 1230 GGTAACACCAATCGGCCCGCA 308 4927 1231 QSYDSSLSGAI 308 4928 1232CAGTCGTATGACAGCAGCCTGAGTGGTGCGATC 309 4929 1233CAGGTGCAGCTGCAGGAGTCCGGAGCTGAGGTGAAGATGCGTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTAGTCACTATGGTATCAGTTGGGTGCGACAGGCCCCTGGACAAGGGCTCGAGTGGATGGGATTTATCAGCGCTTACAATCATAACACAAAGTATGCACAGACCGTCCAGGGCAGAGTCACCTTGAGCACAGACACATCCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAGACCTGACGACACGGCCATGTATTACTGTGCGAGAGAACCCCCGAGTGACGATGCTGCAAGGCTCTTTGACTACTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA 309 4930 1234QVQLQESGAEVKMRGASVKVSCKASGYTFSHYGISWVRQAPGQGLEWMGFISAYNHNTKYAQTVQGRVTLSTDTSTSTAYMELRSLRPDDTAMYYCAREPPSDDAARLFDYWGQGTLVTVSS 309 4931 1235 YTFSHYGIS 309 4932 1236TACACCTTTAGTCACTATGGTATCAGT 309 4933 1237 FISAYNHNTKYAQTVQG 309 49341238 TTTATCAGCGCTTACAATCATAACACAAAGTATGCACAGACCGTCCA GGGC 309 4935 1239AREPPSDDAARLFDY 309 4936 1240GCGAGAGAACCCCCGAGTGACGATGCTGCAAGGCTCTTTGACTAC 309 4937 1241GAAACGACACTCACGCAGTCTCCACGCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTGTACAGTGAAGGAAACACCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTATTGCATGCAAGGTACACAGTGGCCTGTGACATTCGGCCAAGGGACCAAGGTGGAAAT CAAA 309 4938 1242ETTLTQSPRSLPVTLGQPASISCRSSQSLVYSEGNTYLSWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGTQWP VTFGQGTKVEIK 309 49391243 RSSQSLVYSEGNTYLS 309 4940 1244AGGTCTAGTCAAAGCCTCGTGTACAGTGAAGGAAACACCTACTTGAG T 309 4941 1245 KVSNRDS309 4942 1246 AAGGTTTCTAACCGGGACTCT 309 4943 1247 MQGTQWPVT 309 49441248 ATGCAAGGTACACAGTGGCCTGTGACA 310 4945 1249CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAGGGTCTCCTGCAAGGTTTACGGTCACACCCTCAGTGAATTATCCATGCACTGGGTGCGACAGGGTCCTGAAGGAGGCCTTGAGTGGATGGGAGCTTTTGATCATGAAGATGGTGAAGGAATCTACCCACAGAAGTTCCAGGGCAGAATCACCATGACCGCGGACATATCGACAGACACAGCCCACATGGAACTGAGGAGCCTCAGATCTGAGGACACGGCCGTTTATTACTGTGCAACACCGACCCCGGTTGGAGCAACGGACTTCTGGGGCCAG GGAACCCTGGTCACCGTCTCCTCA310 4946 1250 QVQLVQSGAEVKKPGASVRVSCKVYGHTLSELSMHWVRQGPEGGLEWMGAFDHEDGEGIYPQKFQGRITMTADISTDTAHMELRSLRSEDTAVYYC ATPTPVGATDFWGQGTLVTVSS310 4947 1251 HTLSELSMH 310 4948 1252 CACACCCTCAGTGAATTATCCATGCAC 3104949 1253 AFDHEDGEGIYPQKFQG 310 4950 1254GCTTTTGATCATGAAGATGGTGAAGGAATCTACCCACAGAAGTTCCA GGGC 310 4951 1255ATPTPVGATDF 310 4952 1256 GCAACACCGACCCCGGTTGGAGCAACGGACTTC 310 49531257 GACATCCGGGTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTACTTAAATTGGTATCAACAGAAACCAGGAAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCACTTTGCAGAGGGGGGGCCCATCAAGATTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCAGCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTATTGTCAACAGACTTACATTATTCCATACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 310 4954 1258DIRVTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASTLQRGGPSRFSGSGSGTDFTLSISSLQPEDFATYYCQQTYIIPYTFGQGTK LEIK 310 4955 1259RASQSISSYLN 310 4956 1260 CGGGCAAGTCAGAGCATTAGCAGCTACTTAAAT 310 49571261 AASTLQR 310 4958 1262 GCTGCATCCACTTTGCAGAGG 310 4959 1263 QQTYIIPYT310 4960 1264 CAACAGACTTACATTATTCCATACACT 311 4961 1265CAGGTGCAGCTGCAGGAGTCGGGCCCGGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCAGTGTCTCTGGTGGCTCCATCACCAATGTTAATTACTACTGGGGCTGGATCCGCCAGCCCCCCGGGAAGGGCCTGGAGTGGATTGGGAGTATCTATTATAATGGAAACACCTACTACAACCCGTCCCTCCAGAGTCGAGTCACCATGTCCGTGGACACGTCCAAGAACCACTTCTCCCTGAGGCTGACGTCTGTGACCGCCGCAGACACGGCTGTATATTTTTGTGCGAGAGAGGGGCCTAATTGGGAATTGTTGAATGCTTTCGATATCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 311 4962 1266QVQLQESGPGLVKPSETLSLTCSVSGGSITNVNYYWGWIRQPPGKGLEWIGSIYYNGNTYYNPSLQSRVTMSVDTSKNHFSLRLTSVTAADTAVYFCAREGPNWELLNAFDIWGQGTTVTVSS 311 4963 1267 GSITNVNYYWG 311 4964 1268GGCTCCATCACCAATGTTAATTACTACTGGGGC 311 4965 1269 SIYYNGNTYYNPSLQS 3114966 1270 AGTATCTATTATAATGGAAACACCTACTACAACCCGTCCCTCCAGAGT 311 4967 1271AREGPNWELLNAFDI 311 4968 1272GCGAGAGAGGGGCCTAATTGGGAATTGTTGAATGCTTTCGATATC 311 4969 1273GACATCCAGGTGACCCAGCCACCCTCGGTGTCAGTGGCCCCAGGACAGACGGCCAGGATTACCTGTGGGGGAAACAACATTGGAAGTAAAAATGTGCACTGGTACCAGCAGAAGCCAGGCCGGGCCCCTGTCTTGGTCGTCTATGAGGATACCCACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACCATCAGTAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGGTGTGGGATACTAGTAGTGATCATGTGGTATTCGGCGGAGGGACCAAGCTCACCGTCCTA 311 4970 1274DIQVTQPPSVSVAPGQTARITCGGNNIGSKNVHWYQQKPGRAPVLVVYEDTHRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDTSSDHVVF GGGTKLTVL 311 49711275 GGNNIGSKNVH 311 4972 1276 GGGGGAAACAACATTGGAAGTAAAAATGTGCAC 3114973 1277 EDTHRPS 311 4974 1278 GAGGATACCCACCGGCCCTCA 311 4975 1279QVWDTSSDHVV 311 4976 1280 CAGGTGTGGGATACTAGTAGTGATCATGTGGTA 312 49771281 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCCTGGTCAAGCCTGAGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTAGTAGTAGTAGTTACATATACTACGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGTCTCAACAGAATTGGGCTACTACTACATGGACGTCTGGGGCAAAGGGACCACGGTCACTGTCTCCTCA 312 4978 1282QVQLVQSGGGLVKPEGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARVSTELGYYYMDVWGKGTTVTVSS 312 4979 1283 FTFSSYSMN 312 4980 1284TTCACCTTCAGTAGCTATAGCATGAAC 312 4981 1285 SISSSSSYIYYADSVKG 312 49821286 TCCATTAGTAGTAGTAGTAGTTACATATACTACGCAGACTCAGTGAAG GGC 312 4983 1287ARVSTELGYYYMDV 312 4984 1288 GCGAGAGTCTCAACAGAATTGGGCTACTACTACATGGACGTC312 4985 1289 CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTCATCTATGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGCCTGAGTGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTA 312 4986 1290QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSVV FGGGTKLTVL 312 49871291 TGSSSNIGAGYDVH 312 4988 1292ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 312 4989 1293 GNSNRPS 3124990 1294 GGTAACAGCAATCGGCCCTCA 312 4991 1295 QSYDSSLSVV 312 4992 1296CAGTCCTATGACAGCAGCCTGAGTGTGGTA 313 4993 1297CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGATTTCCTGCAAGGCTTCGGGATACCCCTTCAGTTCCTATCCTATGCATTGGGTGCGCCAGGCCCCCGGACAAAGGCTTGAGTGGATGGGATGGATCAACGTTGACAATGAGAACACAAAATATTCATGGAAGTTCCGGGGCAGAGTCACCATTACCAGGGACACATCCGCGAGCACAGTTTACATGGAGCTGAGCAGTCTGATATCTGAAGACACGGCTGTGTATTACTGTGGGAGAGACTGGGACGGGGCGATCCGTGTCTTGGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 313 4994 1298QVQLVQSGAEVKKPGASVKISCKASGYPFSSYPMHWVRQAPGQRLEWMGWINVDNENTKYSWKFRGRVTITRDTSASTVYMELSSLISEDTAVYYCGRDWDGAIRVLDYWGQGTLVTVSS 313 4995 1299 YPFSSYPMH 313 4996 1300TACCCCTTCAGTTCCTATCCTATGCAT 313 4997 1301 WINVDNENTKYSWKFRG 313 49981302 TGGATCAACGTTGACAATGAGAACACAAAATATTCATGGAAGTTCCG GGGC 313 4999 1303GRDWDGAIRVLDY 313 5000 1304 GGGAGAGACTGGGACGGGGCGATCCGTGTCTTGGACTAC 3135001 1305 GATATTGTGATGACTCAGACTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCACCTGCAAGTCCAGCCAGAGTGTTTTATTCAGCTCCGACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCGGGACAGCCTCCTAAATTGCTCATTTACTGGGCATCTATCCGGGAATCCGGGGTCCCTGACCGATTCGGTGGCAGCGGGTCTGGGACACATTTCACTCTCACCATCACCAGCGTGCAGGCTGCAGATGTGGCAGTTTATTACTGTCAGCAATATTATGGTAATTTCCCCACCTTCGGCCAAGGGACACGACTGGAG ATTAAA 313 5002 1306DIVMTQTPDSLAVSLGERATITCKSSQSVLFSSDNKNYLAWYQQKPGQPPKLLIYWASIRESGVPDRFGGSGSGTHFTLTITSVQAADVAVYYCQQYYG NFPTFGQGTRLEIK 3135003 1307 KSSQSVLFSSDNKNYLA 313 5004 1308AAGTCCAGCCAGAGTGTTTTATTCAGCTCCGACAATAAGAACTACTTA GCT 313 5005 1309WASIRES 313 5006 1310 TGGGCATCTATCCGGGAATCC 313 5007 1311 QQYYGNFPT 3135008 1312 CAGCAATATTATGGTAATTTCCCCACC 314 5009 1313CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTTTCCTGTGCAGCCTCTGGATTCACCTTCAGAAACTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTAGCGGCTGCATCGTATGATGGGAGTAGTAAGTACTTTGCAGACGCCGTGAAGGGCCGATTCAGCATCTCCAGAGACAATACCAAGAACACGCTGTCTCTGCAAATGACCAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCAAGAGACCCCGGAGTGGGAAGTTATTATAACGTGGTGGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 314 5010 1314QVQLVQSGGGVVQPGRSLRLSCAASGFTFRNYGMHWVRQAPGKGLEWVAAASYDGSSKYFADAVKGRFSISRDNTKNTLSLQMTSLRAEDTAVYYCARDPGVGSYYNVVGMDVWGQGTTVTVSS 314 5011 1315 FTFRNYGMH 314 5012 1316TTCACCTTCAGAAACTATGGCATGCAC 314 5013 1317 AASYDGSSKYFADAVKG 314 50141318 GCTGCATCGTATGATGGGAGTAGTAAGTACTTTGCAGACGCCGTGAA GGGC 314 5015 1319ARDPGVGSYYNVVGMDV 314 5016 1320GCAAGAGACCCCGGAGTGGGAAGTTATTATAACGTGGTGGGTATGGA CGTC 314 5017 1321GACATCCGGTTGACCCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTATACAGTGATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAGGGTTTCTCACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGAGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGCGTTTATTACTGCATGCAAGGTACACACTGGCCTCCTACGTTCGGCCAAGGGACCAAGGTGGAGAT CAAA 314 5018 1322DIRLTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQRPGQSPRRLIYRVSHRDSGVPDRFSGSESGTDFTLKISRVEAEDVGVYYCMQGTHWP PTFGQGTKVEIK 314 50191323 RSSQSLVYSDGNTYLN 314 5020 1324AGGTCTAGTCAAAGCCTCGTATACAGTGATGGAAACACCTACTTGAA T 314 5021 1325 RVSHRDS314 5022 1326 AGGGTTTCTCACCGGGACTCT 314 5023 1327 MQGTHWPPT 314 50241328 ATGCAAGGTACACACTGGCCTCCTACG 315 5025 1329CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCGCCTGCAAGGTTTCCGGATCCAGCCTCACTGAATTGTCCATTCAATGGGTGCGCTTGCCTCCTGGCAAACGCCTTGAGTGGCTGGGAGCTTTTGATGCTGAAGATGGTGCACCAATCTACTCACCGAAATTCCAGGGCAGAGTCACCATGACCGAGGACAGATCGACAGAGACAGCCTACATGGAGGTGACCAGCCTGAGATCTGAGGACACGGCCCTCTATTACTGTGCGACTCCCCTTCCCGCGGGAGCCCTTGACAAGTGGGGCCAGG GAACCCTGGTCACCGTCTCCTCA315 5026 1330 QVQLVQSGAEVKKPGASVKVACKVSGSSLTELSIQWVRLPPGKRLEWLGAFDAEDGAPIYSPKFQGRVTMTEDRSTETAYMEVTSLRSEDTALYYCAT PLPAGALDKWGQGTLVTVSS315 5027 1331 SSLTELSIQ 315 5028 1332 TCCAGCCTCACTGAATTGTCCATTCAA 3155029 1333 AFDAEDGAPIYSPKFQG 315 5030 1334GCTTTTGATGCTGAAGATGGTGCACCAATCTACTCACCGAAATTCCAG GGC 315 5031 1335ATPLPAGALDK 315 5032 1336 GCGACTCCCCTTCCCGCGGGAGCCCTTGACAAG 315 50331337 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCTTCCGTAGGAGACAGAGTCACCATCTCTTGCCGGGCAAGTCAGACTATAAGCAGATATTTAAATTGGTATCAGGTCAAGCCAGGGACAGCCCCTAAGCTCCTAATCTACGCTGCATCCAGTTTGCAAACTGGGGTCCCATCAAGATTCAGTGCCAGTGGATCTGGGGCAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCGACTTACCACTGTCAACAAACTTACATTATTCCGTACACTTTTGGCCAGGGGACCAAAGTGGATATCAAA 315 5034 1338DIQMTQSPSSLSASVGDRVTISCRASQTISRYLNWYQVKPGTAPKLLIYAASSLQTGVPSRFSASGSGADFTLTISSLQPEDFATYHCQQTYIIPYTFGQGT KVDIK 315 5035 1339RASQTISRYLN 315 5036 1340 CGGGCAAGTCAGACTATAAGCAGATATTTAAAT 315 50371341 AASSLQT 315 5038 1342 GCTGCATCCAGTTTGCAAACT 315 5039 1343 QQTYIIPYT315 5040 1344 CAACAAACTTACATTATTCCGTACACT 316 5041 1345GAGGTGCAGCTGGTGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGATGTCCTCATCAGCAGTGGTGATTACTACTGGAGTTGGATCCGCCAGTCCCCAGGGAAGGGCCTGGAGTGGCTTGGGTACATCTATTATACCGGGAAGACCAAATATAATCCGTCCCTCGAGAGTCGAATTACCATGTCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAGGTTGAGCTCTGTTACTGCCGCAGACACGGCCGTATATTTCTGTACCAGAGATCTGGGATATAGCACCTCGTCCCCCTCCTTTTACTATGGGATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCT CA 316 5042 1346EVQLVESGPGLVKPSQTLSLTCTVSDVLISSGDYYWSWIRQSPGKGLEWLGYIYYTGKTKYNPSLESRITMSVDTSKNQFSLRLSSVTAADTAVYFCTRDLGYSTSSPSFYYGMDVWGQGTTVTVSS 316 5043 1347 VLISSGDYYWS 316 5044 1348GTCCTCATCAGCAGTGGTGATTACTACTGGAGT 316 5045 1349 YIYYTGKTKYNPSLES 3165046 1350 TACATCTATTATACCGGGAAGACCAAATATAATCCGTCCCTCGAGAGT 316 5047 1351TRDLGYSTSSPSFYYGMDV 316 5048 1352ACCAGAGATCTGGGATATAGCACCTCGTCCCCCTCCTTTTACTATGGG ATGGACGTC 316 5049 1353GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTGGGACCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCTTACAGGGTCACTGGCATCCCAGCCAGGTTCAGTGCCAGTGGGTCTGCGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTTCTGTCAGCAGCGTACCAACTGGCCGATCACCTTCGGCCAGGGGACACGACTGGAGATTAAA 316 5050 1354EIVLTQSPATLSLSPGERATLSCRASQSVGTYLAWYQQKPGQAPRLLIYDASYRVTGIPARFSASGSATDFTLTISSLEPEDFAVYFCQQRTNWPITFGQG TRLEIK 316 5051 1355RASQSVGTYLA 316 5052 1356 AGGGCCAGTCAGAGTGTTGGGACCTACTTAGCC 316 50531357 DASYRVT 316 5054 1358 GATGCATCTTACAGGGTCACT 316 5055 1359 QQRTNWPIT316 5056 1360 CAGCAGCGTACCAACTGGCCGATCACC 317 5057 1361CAGGTCCAGCTTGTGCAGTCTGGACCTGAGGTGAAGAAGCCTGGGGCCTCAGTGACGGTCTCCTGCAAGGCTTCCGGTTACACCTTTAGCCATTACGGTATTAGTTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGGTGGATCAGCGCGTACCATGGTCAGACAAACTATGCACAGAACTTCCAGGGCAGAGTCACCATGACCACAGACACATCCTCGAACACAGCCTACATGGAGGTCAGGAGCCTGAGATCTGACGACACGGCCGTTTATTTCTGTGCGAGAGATGTCTTTTCGAAAACAGCAGCTCGAATCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 317 5058 1362QVQLVQSGPEVKKPGASVTVSCKASGYTFSHYGISWVRQAPGQGLEWMGWISAYHGQTNYAQNFQGRVTMTTDTSSNTAYMEVRSLRSDDTAVYFCARDVFSKTAARIFDYWGQGTLVTVSS 317 5059 1363 YTFSHYGIS 317 5060 1364TACACCTTTAGCCATTACGGTATTAGT 317 5061 1365 WISAYHGQTNYAQNFQG 317 50621366 TGGATCAGCGCGTACCATGGTCAGACAAACTATGCACAGAACTTCCA GGGC 317 5063 1367ARDVFSKTAARIFDY 317 5064 1368GCGAGAGATGTCTTTTCGAAAACAGCAGCTCGAATCTTTGACTAC 317 5065 1369GAAATTGTATTGACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAATATAGTGACGGAAACACCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTCAGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGCTACAGACTGGCCGGTCACGTTCGGCCAAGGGACCAAGCTGGAGAT CAAA 317 5066 1370EIVLTQSPLSLPVTLGQPASISCRSSQSLEYSDGNTYLSWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSQSGTDFTLKISRVEAEDVGVYYCMQATDWP VTFGQGTKLEIK 317 50671371 RSSQSLEYSDGNTYLS 317 5068 1372AGGTCTAGTCAAAGCCTCGAATATAGTGACGGAAACACCTACTTGAG T 317 5069 1373 KVSNRDS317 5070 1374 AAGGTTTCTAACCGGGACTCT 317 5071 1375 MQATDWPVT 317 50721376 ATGCAAGCTACAGACTGGCCGGTCACG 318 5073 1377CAGGTGCAGCTGCAGGAGTCGGGCCCAAGACTGGTGAAGCCTTCGCAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGATTATTACTGGAGTTGGATCCGCCAGCCCCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATTACAGTGGGAGCACCCACTACAACCCGTCCCTCAAGAGTCGAGTTAGCATGTCAGTAGACACGGCCAAGAACCAGTTCTCCCTGAAGCTGACCTCTGTGACTGCCGCAGACACGGCCGTCTATTACTGTGCCAGAGATATCGGCTACGGTGACCACGGGACTGGGTCTTATTACTACGGAATAGAAGACTGGGGCCAAGGGACCACGGTCACCGTC TCCTCA 318 5074 1378QVQLQESGPRLVKPSQTLSLTCTVSGGSISSGDYYWSWIRQPPGKGLEWIGYIYYSGSTHYNPSLKSRVSMSVDTAKNQFSLKLTSVTAADTAVYYCARDIGYGDHGTGSYYYGIEDWGQGTTVTVSS 318 5075 1379 GSISSGDYYWS 318 5076 1380GGCTCCATCAGCAGTGGTGATTATTACTGGAGT 318 5077 1381 YIYYSGSTHYNPSLKS 3185078 1382 TACATCTATTACAGTGGGAGCACCCACTACAACCCGTCCCTCAAGAGT 318 5079 1383ARDIGYGDHGTGSYYYGIED 318 5080 1384GCCAGAGATATCGGCTACGGTGACCACGGGACTGGGTCTTATTACTA CGGAATAGAAGAC 318 50811385 GATATTGTGATGACTCAGACTCCAGCCACCCTGTCTTTGTCTCCAGGGGACAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAATATTATGAGCTACTTAGCCTGGTACCAACACAAACCTGGCCAGCCTCCCAGGCTCCTCATCTATGATGCATCCTACAGGGCCGCTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGAACCAACTGGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA 318 5082 1386DIVMTQTPATLSLSPGDRATLSCRASQNIMSYLAWYQHKPGQPPRLLIYDASYRAAGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRTNWITFGQGT RLEIK 318 5083 1387RASQNIMSYLA 318 5084 1388 AGGGCCAGTCAGAATATTATGAGCTACTTAGCC 318 50851389 DASYRAA 318 5086 1390 GATGCATCCTACAGGGCCGCT 318 5087 1391 QQRTNWIT318 5088 1392 CAGCAGCGAACCAACTGGATCACC 319 5089 1393GAGGTGCAGCTGGTGGAGTCAGGGGGAGGCTTGGTGCAGCGGGGGGGGTCCCTGAGACTCTCGTGTGCGGCCTCTGGATTCACCTTTAGTGGTAATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGCATCTATTGGTGAAAGTGCTACTAGCGCATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGATGATTCGAAGAACACTCTGTATCTCCAAATGAACAGCCTGAGACCCGAGGACACGGCCGTATATTTCTGTGCGAAAGATCGCGTAGGATGGTTCGGGGAGTTCGACGCTTTTGATTTCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA 319 5090 1394EVQLVESGGGLVQRGGSLRLSCAASGFTFSGNAMSWVRQAPGKGLEWVASIGESATSAYYADSVKGRFTISRDDSKNTLYLQMNSLRPEDTAVYFCAKDRVGWFGEFDAFDFWGQGTMVTVSS 319 5091 1395 FTFSGNAMS 319 5092 1396TTCACCTTTAGTGGTAATGCCATGAGC 319 5093 1397 SIGESATSAYYADSVKG 319 50941398 TCTATTGGTGAAAGTGCTACTAGCGCATACTACGCAGACTCCGTGAA GGGC 319 5095 1399AKDRVGWFGEFDAFDF 319 5096 1400GCGAAAGATCGCGTAGGATGGTTCGGGGAGTTCGACGCTTTTGATTTC 319 5097 1401TCCTATGAGCTGACGCAGCCACCCTCAGTGTCAGTGGCCCCAGGAAAGACGGCCACCATTTCCTGTGGGGGAAACAACATTGGAGGTCACAAAGTGCACTGGTACCAGCAGAGGCCAGGCCAGGCCCCTGTCTTGGTCATCTATTATGATAACGTCCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTCTGGAAACACGGCCACCCTGACCATCAGCAGGGTCGAGGCCGGGGATGAGGCCGACTTTTACTGTCAGGTGTGGGATAGTCGTTCTGAACATGTCATATTCGGCGGGGGGACCAAGGTCACCGTCCTA 319 5098 1402SYELTQPPSVSVAPGKTATISCGGNNIGGHKVHWYQQRPGQAPVLVIYYDNVRPSGIPERFSGSNSGNTATLTISRVEAGDEADFYCQVWDSRSEHVIF GGGTKVTVL 319 50991403 GGNNIGGHKVH 319 5100 1404 GGGGGAAACAACATTGGAGGTCACAAAGTGCAC 3195101 1405 YDNVRPS 319 5102 1406 TATGATAACGTCCGGCCCTCA 319 5103 1407QVWDSRSEHVI 319 5104 1408 CAGGTGTGGGATAGTCGTTCTGAACATGTCATA 320 51051409 CAGGTCCAGCTTGTACAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCGTGCAAGACTTCTGGTTACACCTTTTCCAACTACGGTATCAGCTGGCTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGCATGGATCAGCCCTTATAATGGGAACACAAAGTCTGCACAGAGGTTTCAGGGCAGAGTCATCATGACCACAGACACATCCACGAGGACAGCCCACATGGAGGTGAAGAGCCTGAGAACTGACGACACGGCCACATATTACTGTGCGAGAGATCCAGCAGTCGATGCAATACCGATGCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 320 5106 1410QVQLVQSGAEVKKPGASVKVSCKTSGYTFSNYGISWLRQAPGQGLEWMAWISPYNGNTKSAQRFQGRVIMTTDTSTRTAHMEVKSLRTDDTATYYCARDPAVDAIPMLDYWGQGTLVTVSS 320 5107 1411 YTFSNYGIS 320 5108 1412TACACCTTTTCCAACTACGGTATCAGC 320 5109 1413 WISPYNGNTKSAQRFQG 320 51101414 TGGATCAGCCCTTATAATGGGAACACAAAGTCTGCACAGAGGTTTCA GGGC 320 5111 1415ARDPAVDAIPMLDY 320 5112 1416 GCGAGAGATCCAGCAGTCGATGCAATACCGATGCTTGACTAC320 5113 1417 GACATCCAGATGACCCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTGTACACTGATGGAAACACCTACTTGAGCTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAGGGTTTCTCACCGGGACTCTGGGGTCCCAGACAGATTCACCGGCAGTGGGTCAGGCACTGATTTCACACTGATAATCCGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGTACACACTGGCCTCTCACTTTCGGCGGAGGGACCAAGCTGGAGAT CAAA 320 5114 1418DIQMTQSPLSLPVTLGQPASISCRSSQSLVYTDGNTYLSWFQQRPGQSPRRLIYRVSHRDSGVPDRFTGSGSGTDFTLIIRRVEAEDVGVYYCMQGTHWPL TFGGGTKLEIK 320 51151419 RSSQSLVYTDGNTYLS 320 5116 1420AGGTCTAGTCAAAGCCTCGTGTACACTGATGGAAACACCTACTTGAG C 320 5117 1421 RVSHRDS320 5118 1422 AGGGTTTCTCACCGGGACTCT 320 5119 1423 MQGTHWPLT 320 51201424 ATGCAAGGTACACACTGGCCTCTCACT 321 5121 1425CAGGTCCAGCTGGTACAGTCTGGTCCTGCGCTGGTGAAACCCACACAGACCCTCACACTGACCTGCACCTTCGGTGGATTCTCACTCAGCAGACATGGAATGCGTGTGACCTGGATCCGTCAGGCCCCCGGGAAGGCCCTGGAGTGGCTTGGTCACATTGATTGGGATGATGATAAATTCTACAGGACATCTCTGAAGACCAGGCTCACCATCTCCAAGGACCCCTCTAACAATGAGGTGGTCCTGAAAATGACCAACATGGACCACGTGGACACAGCCACGTATTACTGTGCACTGATGAGGCCCTTTTGGAGTCGTGACGACTACTACTATTCCATCGCCGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCA 321 5122 1426QVQLVQSGPALVKPTQTLTLTCTFGGFSLSRHGMRVTWIRQAPGKALEWLGHIDWDDDKFYRTSLKTRLTISKDPSNNEVVLKMTNMDHVDTATYYCALMRPFWSRDDYYYSIAVWGKGTTVTVSS 321 5123 1427 FSLSRHGMRVT 321 5124 1428TTCTCACTCAGCAGACATGGAATGCGTGTGACC 321 5125 1429 HIDWDDDKFYRTSLKT 3215126 1430 CACATTGATTGGGATGATGATAAATTCTACAGGACATCTCTGAAGAC C 321 51271431 ALMRPFWSRDDYYYSIAV 321 5128 1432GCACTGATGAGGCCCTTTTGGAGTCGTGACGACTACTACTATTCCATC GCCGTC 321 5129 1433GATATTGTGCTGACCCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGACAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTCGGCAGCGGCTACGTAACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATTTATGGTGCATCAAACAGGGCCGAAGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCGGACTGGAGTCTGAAGATTTTGTAATTTATTACTGTCAGCTATATCATAGGTCACCTGGCTCTGCGAGTCAAACCGTTTGGACGTTCGGCCAAGGGACCA AGGTGGAAATCAAA 321 51301434 DIVLTQSPGTLSLSPGDRATLSCRASQSVGSGYVTWYQQKPGQAPRLLIYGASNRAEGIPDRFSGSGSGTDFTLTISGLESEDFVIYYCQLYHRSPGSASQ TVWTFGQGTKVEIK 3215131 1435 RASQSVGSGYVT 321 5132 1436AGGGCCAGTCAGAGTGTCGGCAGCGGCTACGTAACC 321 5133 1437 GASNRAE 321 5134 1438GGTGCATCAAACAGGGCCGAA 321 5135 1439 QLYHRSPGSASQTVWT 321 5136 1440CAGCTATATCATAGGTCACCTGGCTCTGCGAGTCAAACCGTTTGGACG 322 5137 1441CAGGTCCAGCTTGTACAGTCTGGACCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAGGGTCTCCTGCGAGGCTTCTGGTTACCCCTTTAGCAATTACGGCATCACCTGGGTGCGCCAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAACGGAAACAGAGACTATCTGCAGAAGTTTCAGGGCAGACTCACCATGACCATAGACACATCCACGAGAACAGCCCACATGGAATTGAGGCGCCTGACATCTGACGACACGGCCGTATATTGGTGTGCGAGAGACACACCCGCCACTGCTGCCCCTCTGCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 322 5138 1442QVQLVQSGPEVKKPGASVRVSCEASGYPFSNYGITWVRQAPGQGLEWMGWISAYNGNRDYLQKFQGRLTMTIDTSTRTAHMELRRLTSDDTAVYWCARDTPATAAPLLDYWGQGTLVTVSS 322 5139 1443 YPFSNYGIT 322 5140 1444TACCCCTTTAGCAATTACGGCATCACC 322 5141 1445 WISAYNGNRDYLQKFQG 322 51421446 TGGATCAGCGCTTACAACGGAAACAGAGACTATCTGCAGAAGTTTCA GGGC 322 5143 1447ARDTPATAAPLLDY 322 5144 1448 GCGAGAGACACACCCGCCACTGCTGCCCCTCTGCTTGACTAC322 5145 1449 GATATTGTGATGACTCAGTCTCCACTCTCCCTGGCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAATTCACTGATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGGTTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGTATTTTCCGGCCGGGGACGTTCGGCCAAGGGACCAAGGTGGAAAT CAAA 322 5146 1450DIVMTQSPLSLAVTLGQPASISCRSSQSLEFTDGNTYLNWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTGFTLKISRVEAEDVGVYYCMQGIFRP GTFGQGTKVEIK 322 51471451 RSSQSLEFTDGNTYLN 322 5148 1452AGGTCTAGTCAAAGCCTCGAATTCACTGATGGAAACACCTACTTGAA T 322 5149 1453 KVSNRDS322 5150 1454 AAGGTTTCTAACCGGGACTCT 322 5151 1455 MQGIFRPGT 322 51521456 ATGCAAGGTATTTTCCGGCCGGGGACG 323 5153 1457CAGGTCCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTGTCCACTATGGTATCAGTTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCATACAATGGTAATACAAACTCTGCACTGAAGTTCCAGGACAGAGTCACCATGACCACAGACCCATCCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCATTTATTACTGTGCGAGAGACTCAGGTTGTTGTAGTGGTTCCACCTCAGACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCA 323 5154 1458QVQLVQSGAEVKKPGASVKVSCKASGYTFVHYGISWVRQAPGQGLEWMGWISAYNGNTNSALKFQDRVTMTTDPSTSTAYMELRSLRSDDTAIYYCARDSGCCSGSTSDVWGKGTTVTVSS 323 5155 1459 YTFVHYGIS 323 5156 1460TACACCTTTGTCCACTATGGTATCAGT 323 5157 1461 WISAYNGNTNSALKFQD 323 51581462 TGGATCAGCGCATACAATGGTAATACAAACTCTGCACTGAAGTTCCA GGAC 323 5159 1463ARDSGCCSGSTSDV 323 5160 1464 GCGAGAGACTCAGGTTGTTGTAGTGGTTCCACCTCAGACGTC323 5161 1465 GATATTGTGATGACTCAGTCTCCACTCTCTTCACCTGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTGCACAGTGATGGAAACACCTACTTGAGTTGGCTTCACCAGAGGCCAGGCCAGCCTCCAAGACTCCTAATTTATAAGATTTCCCACCGGTTCTCTGGGGTCCCAGACAGATTCACTGGCAGTGGGGCAGGGACAGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTCGGGGTTTATTACTGCATGCAAGCTACAGAATTTCCTCCGATGTACACTTTTGGCCAGGGGACCAAGGTG GAGATCAAA 323 5162 1466DIVMTQSPLSSPVTLGQPASISCRSSQSLVHSDGNTYLSWLHQRPGQPPRLLIYKISHRFSGVPDRFTGSGAGTDFTLKISRVEAEDVGVYYCMQATEFPP MYTFGQGTKVEIK 3235163 1467 RSSQSLVHSDGNTYLS 323 5164 1468AGGTCTAGTCAAAGCCTCGTGCACAGTGATGGAAACACCTACTTGAG T 323 5165 1469 KISHRFS323 5166 1470 AAGATTTCCCACCGGTTCTCT 323 5167 1471 MQATEFPPMYT 323 51681472 ATGCAAGCTACAGAATTTCCTCCGATGTACACT 324 5169 1473GAGGTGCAGCTGGTGGAGACGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGACTCCATCAGTGGTTACTACTGGAGCTGGATCCGGCAGTCCCCAGGGAAGGGACTGGAGTGGATTGGCTATATCTATTACAGGGGGAGCACCGACTACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAAACTGAGCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGAGATAATAAACACCATGATTCGGGAAATTATTACGCATACTTTGACCATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 324 5170 1474EVQLVETGPGLVKPSETLSLTCTVSGDSISGYYWSWIRQSPGKGLEWIGYIYYRGSTDYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDNKHHDSGNYYAYFDHWGQGTLVTVSS 324 5171 1475 DSISGYYWS 324 5172 1476GACTCCATCAGTGGTTACTACTGGAGC 324 5173 1477 YIYYRGSTDYNPSLKS 324 5174 1478TATATCTATTACAGGGGGAGCACCGACTACAACCCCTCCCTCAAGAG T 324 5175 1479ARDNKHHDSGNYYAYFDH 324 5176 1480GCGAGAGATAATAAACACCATGATTCGGGAAATTATTACGCATACTT TGACCAT 324 5177 1481GATATTGTGATGACTCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAACATTAACACCTTTTTAAATTGGTATCAGCACAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGGTGCATCCCGTTTGCAGAGTGGGGTCCCATCAAGGTTCACTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTCCTGTCAACAGAGTTACACTACCCGGCTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA 324 5178 1482DIVMTQSPSSLSASVGDRVTITCRASQNINTFLNWYQHKPGKAPKLLIYGASRLQSGVPSRFTGSGSGTDFTLTISSLQPEDFATYSCQQSYTTRLTFGGG TKVEIK 324 5179 1483RASQNINTFLN 324 5180 1484 CGGGCAAGTCAGAACATTAACACCTTTTTAAAT 324 51811485 GASRLQS 324 5182 1486 GGTGCATCCCGTTTGCAGAGT 324 5183 1487 QQSYTTRLT324 5184 1488 CAACAGAGTTACACTACCCGGCTCACT 325 5185 1489CAGGTCCAGCTGGTGCAGTCTGGGACTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGATTTCCTGCAAGACTTCTGGATACACCTTCACTAATAATGTAATTCAATGGGTGCGCCAGGCCCCCGGACAAAGGCTTGAGTGGATGGGATGGATCAGCGCTGGCAATGGTTACACAAAATATTCAGACAAGTTCCAGGACAGAGTCACCATTACCAGGGACACATCCGCGAGCACAGCCTACATGGAGGTGAGCAGCCTGACATCTGAAGACACGGCTATGTATTACTGTGCGAGACAAGTCTCGACTAGTGGCTGGCACGCAACGTCACACCGGTTCGCCCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 325 5186 1490QVQLVQSGTEVKKPGASVKISCKTSGYTFTNNVIQWVRQAPGQRLEWMGWISAGNGYTKYSDKFQDRVTITRDTSASTAYMEVSSLTSEDTAMYYCARQVSTSGWHATSHRFAPWGQGTLVTVSS 325 5187 1491 YTFTNNVIQ 325 5188 1492TACACCTTCACTAATAATGTAATTCAA 325 5189 1493 WISAGNGYTKYSDKFQD 325 51901494 TGGATCAGCGCTGGCAATGGTTACACAAAATATTCAGACAAGTTCCA GGAC 325 5191 1495ARQVSTSGWHATSHRFAP 325 5192 1496GCGAGACAAGTCTCGACTAGTGGCTGGCACGCAACGTCACACCGGTT CGCCCCC 325 5193 1497GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCGAGTCAGGGCATTAGTAGATATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTACGATGCATCCAATTTGGAAACAGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGACACATTTTACTTTAACCATCAGCAGCCTGCAGCCTGAAGATATTGCAACATATTACTGTCAACAGTATGATAATCTCCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA 325 5194 1498DIQMTQSPSSLSASVGDRVTITCQASQGISRYLNWYQQKPGKAPNLLIYDASNLETGVPSRFSGSGSGTHFTLTISSLQPEDIATYYCQQYDNLPLTFGGG TKVEIK 325 5195 1499QASQGISRYLN 325 5196 1500 CAGGCGAGTCAGGGCATTAGTAGATATTTAAAT 325 51971501 DASNLET 325 5198 1502 GATGCATCCAATTTGGAAACA 325 5199 1503 QQYDNLPLT325 5200 1504 CAACAGTATGATAATCTCCCGCTCACT 326 5201 1505GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGAAGCCTCTGGATTCACCTTCAGTAGTTTTAGCATGCACTGGGTCCGCCAGGCTCCGGGCAAGGGGCTGGAGTGGGTGGCAGTGATTTTATATGATGGGAGTAATCAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTTTATCTGCAAATGAACACCCTGAGAGCTGAGGACACGGCTATGTATTACTGTGCGAAATCATCATCGTCCCATGTTAACTCTCGACAAGACAAATGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA 326 5202 1506EVQLVESGGGVVQPGRSLRLSCEASGFTFSSFSMHWVRQAPGKGLEWVAVILYDGSNQYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAMYYCAKSSSSHVNSRQDKWGQGTLVTVSS 326 5203 1507 FTFSSFSMH 326 5204 1508TTCACCTTCAGTAGTTTTAGCATGCAC 326 5205 1509 VILYDGSNQYYADSVKG 326 52061510 GTGATTTTATATGATGGGAGTAATCAATACTATGCAGACTCCGTGAAG GGC 326 5207 1511AKSSSSHVNSRQDK 326 5208 1512 GCGAAATCATCATCGTCCCATGTTAACTCTCGACAAGACAAA326 5209 1513 GAAATTGTATTGACACAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGGTGGTTGGCCTGGTATCAGCAGAAACCAGGGGAAGCCCCTAAACTCCTGATCCACACGGCGTCTACATTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGCTCTGGGACAGAATTCACTCTCACCATCAACAGCCTGCAGCCTGATGATCTTGCAACTTATTACTGCCAACAGTATTATAATTGGTGGACGTTCGGCCAAGGGACCAAGGTGGAGATCAAA 326 5210 1514EIVLTQSPSTLSASVGDRVTITCRASQSISRWLAWYQQKPGEAPKLLIHTASTLESGVPSRFSGSGSGTEFTLTINSLQPDDLATYYCQQYYNWWTFGQGT KVEIK 326 5211 1515RASQSISRWLA 326 5212 1516 CGGGCCAGTCAGAGTATTAGTAGGTGGTTGGCC 326 52131517 TASTLES 326 5214 1518 ACGGCGTCTACATTAGAAAGT 326 5215 1519 QQYYNWWT326 5216 1520 CAACAGTATTATAATTGGTGGACG 327 5217 1521GAGGTGCAGCTGTTGGAGTCCGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGATCTCCTGCAAGGCCTCTGGTTACATCTTTACCAGTTATGGTGTCAGTTGGGTGCGACAGGCCCCTGGACAAGGGCTTAAGTGGATGGGATGGATCAGCGGTTACAATGGTAACACATACTATGACCAGAAATTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAACACAGCCTACATGGAGTTGAGGAGCCTGACATCTGACGACACGGCCGTATATTACTGTGCGAGAGATTCCTTTTCAGAGACTGGGACTGGATTTCCTGACTTCTGGGGCCAGGGCACCCTGGTCACCGTCTCTTCA 327 5218 1522EVQLLESGAEVKKPGASVKISCKASGYIFTSYGVSWVRQAPGQGLKWMGWISGYNGNTYYDQKFQGRVTMTTDTSTNTAYMELRSLTSDDTAVYYCARDSFSETGTGFPDFWGQGTLVTVSS 327 5219 1523 YIFTSYGVS 327 5220 1524TACATCTTTACCAGTTATGGTGTCAGT 327 5221 1525 WISGYNGNTYYDQKFQG 327 52221526 TGGATCAGCGGTTACAATGGTAACACATACTATGACCAGAAATTCCA GGGC 327 5223 1527ARDSFSETGTGFPDF 327 5224 1528GCGAGAGATTCCTTTTCAGAGACTGGGACTGGATTTCCTGACTTC 327 5225 1529GAAATTGTGTTGACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCCGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGAGTTTATTACTGCATGCAAGCCACACACCGGCCTCGCACGTTCGGCCAAGGGACCAAAGTGGATAT CAAA 327 5226 1530EIVLTQSPLSLPVTLGQPASISCRSSQSLEYSDGNTYLNWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQATHRP RTFGQGTKVDIK 327 52271531 RSSQSLEYSDGNTYLN 327 5228 1532AGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACACCTACTTGAA T 327 5229 1533 KVSNRDS327 5230 1534 AAGGTTTCTAACCGGGACTCT 327 5231 1535 MQATHRPRT 327 52321536 ATGCAAGCCACACACCGGCCTCGCACG 328 5233 1537CAGGTCCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAAGATCTCCTGTAAGGGTTTTGGATACAGCTTTAACAGTTACTGGATCGCCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGCATGGGCATCATCTATCCTGGCGACTCTGATACCAGATACAGCCCGTCCTTCCAAGGGCAGGTCACCATCTCAGTCGACAAGTCCATCACTACCGCCTACCTGCAGTGGAGCAGCCTGAAGGTCTCGGACACCGCCATGTATTACTGTGCGAAAAGTAATGTGGGGAATACAGGTTGGAACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 328 5234 1538QVQLVQSGAEVKKPGESLKISCKGFGYSFNSYWIAWVRQMPGKGLECMGIIYPGDSDTRYSPSFQGQVTISVDKSITTAYLQWSSLKVSDTAMYYCAK SNVGNTGWNYWGQGTLVTVSS328 5235 1539 YSFNSYWIA 328 5236 1540 TACAGCTTTAACAGTTACTGGATCGCC 3285237 1541 IIYPGDSDTRYSPSFQG 328 5238 1542ATCATCTATCCTGGCGACTCTGATACCAGATACAGCCCGTCCTTCCAA GGG 328 5239 1543AKSNVGNTGWNY 328 5240 1544 GCGAAAAGTAATGTGGGGAATACAGGTTGGAACTAC 328 52411545 GAAATTGTATTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCACAGTGTTGCCACCGACCTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAAGAGGGCCACTGACGTCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATGTTGCAGTTTATTACTGTCAGGAAGTTAGGAACTGGCCTCCGTGCACTTTTGGCCAGGGGACCAAAGTGGATATCAAA 328 5242 1546EIVLTQSPATLSLSPGERATLSCRASHSVATDLAWYQQKPGQAPRLLIYDASKRATDVPARFSGSGSGTDFTLTISSLEPEDVAVYYCQEVRNWPPCTFG QGTKVDIK 328 52431547 RASHSVATDLA 328 5244 1548 AGGGCCAGTCACAGTGTTGCCACCGACCTAGCC 3285245 1549 DASKRAT 328 5246 1550 GATGCATCCAAGAGGGCCACT 328 5247 1551QEVRNWPPCT 328 5248 1552 CAGGAAGTTAGGAACTGGCCTCCGTGCACT 329 5249 1553GAGGTGCAGCTGCAGGAGTCCGGCTCTCGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCTCTGTCTCTGGTGGCTCCCTCAACGCAGGCGGTTACCTGTGGAGCTGGATCCGTCAGCCACCAGGGAAGGGCCTGGAGTGGGTTGGGTACATCTATCCTAGTGGGACTACCTACTACAACCCGTCCCTGCAGAGTCGAATCAGCATTTCACAAGACAGGTCCAGGAACCAGTTCTCCCTGAGCGTAGCGTCTGTGACCGCCGCGGACACGGCCGTCTATTACTGTGCCAGATGTGGGAATGAGTACGGTGAGGTCCATCCTTTTGATATTTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 329 5250 1554EVQLQESGSRLVKPSQTLSLTCSVSGGSLNAGGYLWSWIRQPPGKGLEWVGYIYPSGTTYYNPSLQSRISISQDRSRNQFSLSVASVTAADTAVYYCARCGNEYGEVHPFDIWGQGTTVTVSS 329 5251 1555 GSLNAGGYLWS 329 5252 1556GGCTCCCTCAACGCAGGCGGTTACCTGTGGAGC 329 5253 1557 YIYPSGTTYYNPSLQS 3295254 1558 TACATCTATCCTAGTGGGACTACCTACTACAACCCGTCCCTGCAGAGT 329 5255 1559ARCGNEYGEVHPFDI 329 5256 1560GCCAGATGTGGGAATGAGTACGGTGAGGTCCATCCTTTTGATATT 329 5257 1561GAAATTGTATTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCCGGGGCAGTCCTATTGTTGGCAACAACTACTTAGCCTGGTACCAGCAGAAGCCTGGCCAGGCTCCCAGGCTCCTCATCTATGCTGCATCCATCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTAGAGCCTGAAGATTTTGCAGTCTATTACTGTCAGCAATATGGCAGCTCACCGTGGACGTTCGGCCAAGGGACCAAAGTGGATATCAAA 329 5258 1562EIVLTQSPGTLSLSPGERATLSCRGSPIVGNNYLAWYQQKPGQAPRLLIYAASIRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQG TKVDIK 329 5259 1563RGSPIVGNNYLA 329 5260 1564 CGGGGCAGTCCTATTGTTGGCAACAACTACTTAGCC 329 52611565 AASIRAT 329 5262 1566 GCTGCATCCATCAGGGCCACT 329 5263 1567 QQYGSSPWT329 5264 1568 CAGCAATATGGCAGCTCACCGTGGACG 330 5265 1569CAGGTGCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACATCTTTACCAGTTATGGTGTCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTAAGTGGATGGGATGGATCAGCGGTTACAATGGTAACACAAACTATGACCAGAAACTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGACATCTGACGACACGGCCGTTTATTACTGTGCGAGAGATTCATTTTCAGAGACTGGGACTGGGTTTCCTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 330 5266 1570QVQLVQSGAEVKKPGASVKVSCKASGYIFTSYGVSWVRQAPGQGLKWMGWISGYNGNTNYDQKLQGRVTMTTDTSTSTAYMELRSLTSDDTAVYYCARDSFSETGTGFPDFWGQGTLVTVSS 330 5267 1571 YIFTSYGVS 330 5268 1572TACATCTTTACCAGTTATGGTGTCAGC 330 5269 1573 WISGYNGNTNYDQKLQG 330 52701574 TGGATCAGCGGTTACAATGGTAACACAAACTATGACCAGAAACTCCA GGGC 330 5271 1575ARDSFSETGTGFPDF 330 5272 1576GCGAGAGATTCATTTTCAGAGACTGGGACTGGGTTTCCTGACTTC 330 5273 1577GACATCCAGATGACCCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGAGTTTATTACTGCATGCAAGCCACACACCGGCCTCGCACGTTCGGCCAAGGGACCAAGCTGGAGAT CAAA 330 5274 1578DIQMTQSPLSLPVTLGQPASISCRSSQSLEYSDGNTYLNWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQATHRP RTFGQGTKLEIK 330 52751579 RSSQSLEYSDGNTYLN 330 5276 1580AGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACACCTACTTGAA T 330 5277 1581 KVSNRDS330 5278 1582 AAGGTTTCTAACCGGGACTCT 330 5279 1583 MQATHRPRT 330 52801584 ATGCAAGCCACACACCGGCCTCGCACG 331 5281 1585GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGTTTTTCTATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCACTTATATCATCTGACGAGAGGAATTCATACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATAAGCAGGCTGAAAGTCGAGGACACGGCTGTGTATTATTGTGCGAGAGAGGCATACGAAGAGTGGGAGCTAACGATGGGGAACCTTGACCACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 331 5282 1586EVQLVESGGGVVQPGRSLRLSCAASGFTFSSFSMHWVRQAPGKGLEWVALISSDERNSYYADSVKGRFTISRDNSKNTLYLQISRLKVEDTAVYYCAREAYEEWELTMGNLDHWGQGTLVTVSS 331 5283 1587 FTFSSFSMH 331 5284 1588TTCACCTTCAGTAGTTTTTCTATGCAC 331 5285 1589 LISSDERNSYYADSVKG 331 52861590 CTTATATCATCTGACGAGAGGAATTCATACTACGCAGACTCCGTGAA GGGC 331 5287 1591AREAYEEWELTMGNLDH 331 5288 1592GCGAGAGAGGCATACGAAGAGTGGGAGCTAACGATGGGGAACCTTG ACCAC 331 5289 1593GACATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTGGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTGATCTATAGTACATACAGCTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATCGTTACCCCTTCACTTTCGGCCCTGGGACCAAGCTGGAGATCAAA 331 5290 1594DIQLTQSPSSLSASVGDRVTITCRASQGIGNDLGWYQQKPGKAPKRLIYSTYSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNRYPFTFGPG TKLEIK 331 5291 1595RASQGIGNDLG 331 5292 1596 CGGGCAAGTCAGGGCATTGGAAATGATTTAGGC 331 52931597 STYSLQS 331 5294 1598 AGTACATACAGCTTGCAAAGT 331 5295 1599 LQHNRYPFT331 5296 1600 CTACAGCATAATCGTTACCCCTTCACT 332 5297 1601CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGCCTCCGTCACCACTAATACTTACTACTGGACCTGGATCCGGCAGCCCCCAGGGAAGGAACTGGAGTGGATTGGATATATCCATCACACTGGGAACACCCACTACAACCCCTCCCTCGAGAGTCGACTCACCATGTCACTAGACACGTCCAGGAACCAGTTCTCTCTGAACCTTAGGTCTGCCACCACTGCGGACACGGCCGTTTATTACTGTGCGAGAGGCGAACATTTTGCGTACTGGTGGGGAAACTGGGGCCAGGGAGCCCTGGTCACCGTCTCCTCA 332 5298 1602QVQLQESGPGLVKPSETLSLTCTVSGASVTTNTYYWTWIRQPPGKELEWIGYIHHTGNTHYNPSLESRLTMSLDTSRNQFSLNLRSATTADTAVYYCAR GEHFAYWWGNWGQGALVTVSS332 5299 1603 ASVTTNTYYWT 332 5300 1604GCCTCCGTCACCACTAATACTTACTACTGGACC 332 5301 1605 YIHHTGNTHYNPSLES 3325302 1606 TATATCCATCACACTGGGAACACCCACTACAACCCCTCCCTCGAGAGT 332 5303 1607ARGEHFAYWWGN 332 5304 1608 GCGAGAGGCGAACATTTTGCGTACTGGTGGGGAAAC 332 53051609 GACATCCGGGTGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTGCCAGATGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAGGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATATGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTACTGTCAACAGGCTAACAGTTTTCCTCGAACGTTCGGCCAAGGGACCAAGGTGGAGATCAAA 332 5306 1610DIRVTQSPSSVSASVGDRVTITCRASQGIARWLAWYQQKPGKAPKLLIYAASSLQGGVPSRFSGSGYGTDFTLTISSLQPEDFATYYCQQANSFPRTFGQG TKVEIK 332 5307 1611RASQGIARWLA 332 5308 1612 CGGGCGAGTCAGGGTATTGCCAGATGGTTAGCC 332 53091613 AASSLQG 332 5310 1614 GCTGCATCCAGTTTGCAAGGT 332 5311 1615 QQANSFPRT332 5312 1616 CAACAGGCTAACAGTTTTCCTCGAACG 333 5313 1617CAGGTCCAGCTTGTACAGTCTGGGCCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCGAGGCTTCTGGATACACCTTCACCGACTTCTTTGTGCACTGGGTGCGACAGGCCCCTGGTGAGGGGCTTGTGTGGTTGGGATGGGTCAACCCTCTCAGTGGCGCCACAAAGTATGCACAGAACTTTCAGGGCAGGGTCACCATGACCAGTGACACGTCCATCACCACAGCCTACATGGCACTGAGCAGCCTGAGACATGACGACACGGCCGTCTATTACTGTACGAGCCAGACTTCACCTTATACCCCGGGCGCTATGGGCGTTTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 333 5314 1618QVQLVQSGPEVKKPGASVKVSCEASGYTFTDFFVHWVRQAPGEGLVWLGWVNPLSGATKYAQNFQGRVTMTSDTSITTAYMALSSLRHDDTAVYYCTSQTSPYTPGAMGVWGQGTTVTVSS 333 5315 1619 YTFTDFFVH 333 5316 1620TACACCTTCACCGACTTCTTTGTGCAC 333 5317 1621 WVNPLSGATKYAQNFQG 333 53181622 TGGGTCAACCCTCTCAGTGGCGCCACAAAGTATGCACAGAACTTTCA GGGC 333 5319 1623TSQTSPYTPGAMGV 333 5320 1624 ACGAGCCAGACTTCACCTTATACCCCGGGCGCTATGGGCGTT333 5321 1625 GACATCCGGGTGACCCAGTCTCCAGCCTCCCTGTCTGCATTTGTTGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCCGGCCATTAGCGGCTATTTAAGTTGGTATCAGCAGAAGGCAGGCAAAGCCCCTAAGATCCTGATCTATGATGCATCTAATTTGTATAGTGGGGCCCCATCACGGTTCAGTGGCAGTAGATCTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGACTTACAATGGCCTAATCGCTTTCGGCCCTGGGACCAAGGTGGAAATCAAA 333 5322 1626DIRVTQSPASLSAFVGDRVTITCRASPAISGYLSWYQQKAGKAPKILIYDASNLYSGAPSRFSGSRSGTDFTLTITSLQPEDFATYYCQQTYNGLIAFGPGT KVEIK 333 5323 1627RASPAISGYLS 333 5324 1628 CGGGCAAGTCCGGCCATTAGCGGCTATTTAAGT 333 53251629 DASNLYS 333 5326 1630 GATGCATCTAATTTGTATAGT 333 5327 1631 QQTYNGLIA333 5328 1632 CAACAGACTTACAATGGCCTAATCGCT 334 5329 1633GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAAGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAATACCTATGCTATACACTGGGTCCGCCAGGCTCCAGGCAAGGGCCTGGAGTGGGTGGCAGCTATATCATATGATGGAAGCAATGAATACTACTCAAACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGTACACGCTGGAGCTGCAAATGAACAGCCTGAGACCTGAGGACACGGCTGTGTATTACTGTGCGAGAGGCGCCTCCTACTACTATGTGAGTAGTGACCTTGGCTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 334 5330 1634EVQLLESGGGVVQPGKSLRLSCAASGFTFNTYAIHWVRQAPGKGLEWVAAISYDGSNEYYSNSVKGRFTISRDNSKYTLELQMNSLRPEDTAVYYCARGASYYYVSSDLGYWGQGTLVTVSS 334 5331 1635 FTFNTYAIH 334 5332 1636TTCACCTTCAATACCTATGCTATACAC 334 5333 1637 AISYDGSNEYYSNSVKG 334 53341638 GCTATATCATATGATGGAAGCAATGAATACTACTCAAACTCCGTGAA GGGC 334 5335 1639ARGASYYYVSSDLGY 334 5336 1640GCGAGAGGCGCCTCCTACTACTATGTGAGTAGTGACCTTGGCTAC 334 5337 1641CAGTCTGTCGTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGTCAGGTTATGATGTGCACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAAGTCGTCATCTATGGTAACATCAATCGGCCCTCAGGGGTCCCTGAGCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCCTGAGTGCCTCTTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCT A 334 5338 1642QSVVTQPPSVSGAPGQRVTISCTGSSSNIGSGYDVHWYQQLPGTAPKVVIYGNINRPSGVPERFSGSKSGTSASLAITGLQAEDEADYYCQSYDSLSASW VFGGGTKLTVL 334 53391643 TGSSSNIGSGYDVH 334 5340 1644ACTGGGAGCAGCTCCAACATCGGGTCAGGTTATGATGTGCAC 334 5341 1645 GNINRPS 3345342 1646 GGTAACATCAATCGGCCCTCA 334 5343 1647 QSYDSLSASWV 334 5344 1648CAGTCCTATGACAGCCTGAGTGCCTCTTGGGTG 335 5345 1649CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCCTCTGGAGGCACCTTCAGCGGCCACGCTATCAACTGGGTGCGACAGGCCCCTGGACAAGGGCTCGAATGGATGGGAGGGATCATCCATATATTTGGGACAGTAAACTACGCTCCGAAGTTCCAGGGCAGAGTCACGATCACCGCGGACGCATCCACGGGCACAGTTTACATGGAGTTGAGCAGCCTGATATCTGAGGACACGGCCGTATATTATTGTGCGAGAGATGCTTACGAAGTGTGGACTGGTTCTTATCTCCCCCCTTTTGACGACTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA 335 5346 1650QVQLVQSGAEVKKPGSSVKVSCKASGGTFSGHAINWVRQAPGQGLEWMGGIIHIFGTVNYAPKFQGRVTITADASTGTVYMELSSLISEDTAVYYCARDAYEVWTGSYLPPFDDWGQGTLVTVSS 335 5347 1651 GTFSGHAIN 335 5348 1652GGCACCTTCAGCGGCCACGCTATCAAC 335 5349 1653 GIIHIFGTVNYAPKFQG 335 53501654 GGGATCATCCATATATTTGGGACAGTAAACTACGCTCCGAAGTTCCA GGGC 335 5351 1655ARDAYEVWTGSYLPPFDD 335 5352 1656GCGAGAGATGCTTACGAAGTGTGGACTGGTTCTTATCTCCCCCCTTTT GACGAC 335 5353 1657GATATTGTGATGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCCGGGGACAGAGTCACCCTCTCCTGCAGGGCCAGTCAGACTGTTACAAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATTCACCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCAGCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTATATTATTGTCAGCAGTATGGTAGCTCATTCCTCACTTTCGGCGGAGGGACCAAAGTGGATATCAAA 335 5354 1658DIVMTQSPGTLSLSPGDRVTLSCRASQTVTSSYLAWYQQKPGQAPRLLIYGAFTRATGIPDRFSGSGSGTDFTLSISRLEPEDFAVYYCQQYGSSFLTFGG GTKVDIK 335 53551659 RASQTVTSSYLA 335 5356 1660 AGGGCCAGTCAGACTGTTACAAGCAGCTACTTAGCC 3355357 1661 GAFTRAT 335 5358 1662 GGTGCATTCACCAGGGCCACT 335 5359 1663QQYGSSFLT 335 5360 1664 CAGCAGTATGGTAGCTCATTCCTCACT 336 5361 1665GAGGTGCAGCTGGTGGAATCTGGGGGAGGCCTGGTCAGGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGTCTCAGTAGTTACGGCATGAGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTGGAGTGGGTCTCATCCATTACTGCCGGCAGTAGTTACATAAATTACGCTGACTCAGTGAAGGGCCGGTTCACCATCTCCAGAGACAACGCCAAGAGTTCACTGTTCCTGCAAATGACCAGCCTGAGAGTCGAGGACACGGCTGTTTATTTCTGTGTGAGAGAGGCGTATGCCAGCTCGTCGGCCCTTTACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 336 5362 1666EVQLVESGGGLVRPGGSLRLSCAASGFSLSSYGMSWVRQAPGKGLEWVSSITAGSSYINYADSVKGRFTISRDNAKSSLFLQMTSLRVEDTAVYFCVREAYASSSALYWFDPWGQGTLVTVSS 336 5363 1667 FSLSSYGMS 336 5364 1668TTCAGTCTCAGTAGTTACGGCATGAGT 336 5365 1669 SITAGSSYINYADSVKG 336 53661670 TCCATTACTGCCGGCAGTAGTTACATAAATTACGCTGACTCAGTGAAG GGC 336 5367 1671VREAYASSSALYWFDP 336 5368 1672GTGAGAGAGGCGTATGCCAGCTCGTCGGCCCTTTACTGGTTCGACCCC 336 5369 1673CAGTCTGTCCTGACGCAGCCGCCCTCAGTCTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAATCTCGGGGCGGGTTATGTTGTTCACTGGTACCAGCAACTTCCAGGAACATCCCCCAAACTCCTCATCTATGGTAACACCGATCGGCCCTCAGGGGTCCCCGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGTAGCCTGAGTGGCTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA 336 5370 1674QSVLTQPPSVSGAPGQRVTISCTGSSSNLGAGYVVHWYQQLPGTSPKLLIYGNTDRPSGVPDRFSGSKSGTSASLAISGLQAEDEADYYCQSYDSSLSGW VFGGGTKLTVL 336 53711675 TGSSSNLGAGYVVH 336 5372 1676ACTGGGAGCAGCTCCAATCTCGGGGCGGGTTATGTTGTTCAC 336 5373 1677 GNTDRPS 3365374 1678 GGTAACACCGATCGGCCCTCA 336 5375 1679 QSYDSSLSGWV 336 5376 1680CAGTCCTATGACAGTAGCCTGAGTGGCTGGGTG 337 5377 1681GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTAGTACAGCCTGGGGGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAATACCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGATTGGAGTGGCTTTCATTCATTAGTAGTAGTAGTCATACCCTATACTACGCAGACTCTGTGAAGGGCCGATTCACCGTCTTCAGAGACAATGCCAAGCACTCGCTCTTTCTGCAAATGAACGGCCTGAGAGACGAGGACACGGCTGTTTATTTCTGTGCGAGATCCCTTGGTTCGGGGAATTATGATAACGAAGATCAGACATTTTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGG TCACCGTCTCCTCA 337 53781682 EVQLVESGGGLVQPGGSLRLSCAASGFSFNTYSMNWVRQAPGKGLEWLSFISSSSHTLYYADSVKGRFTVFRDNAKHSLFLQMNGLRDEDTAVYFCARSLGSGNYDNEDQTFYYYYGMDVWGQGTTVTVSS 337 5379 1683 FSFNTYSMN 337 5380 1684TTCAGCTTCAATACCTATAGCATGAAC 337 5381 1685 FISSSSHTLYYADSVKG 337 53821686 TTCATTAGTAGTAGTAGTCATACCCTATACTACGCAGACTCTGTGAAG GGC 337 5383 1687ARSLGSGNYDNEDQTFYYYYGMDV 337 5384 1688GCGAGATCCCTTGGTTCGGGGAATTATGATAACGAAGATCAGACATTTTACTACTACTACGGTATGGACGTC 337 5385 1689GAAACGACACTCACGCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATATCCTGCCGGTCTAGTCAGAGCCTCCTGTTTCATAGTAATGGACACAATTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAACTCCTGATCCATTTGGGTTCTAATCGGGCCTCCGGAGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGCCTGAGGATGTTGGGGTTTATTACTGTATGCAAGCTCTACAAACTCCGTACACTTTTGGCCAGGGGACCAAGGTGGA GATCAAA 337 5386 1690ETTLTQSPLSLPVTPGEPASISCRSSQSLLFHSNGHNYLDWYLQKPGQSPQLLIHLGSNRASGVPDRFSGSGSGTDFTLKISRVEPEDVGVYYCMQALQTP YTFGQGTKVEIK 337 53871691 RSSQSLLFHSNGHNYLD 337 5388 1692CGGTCTAGTCAGAGCCTCCTGTTTCATAGTAATGGACACAATTATTTG GAT 337 5389 1693LGSNRAS 337 5390 1694 TTGGGTTCTAATCGGGCCTCC 337 5391 1695 MQALQTPYT 3375392 1696 ATGCAAGCTCTACAAACTCCGTACACT 338 5393 1697CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACGGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGTCTCCGTCACCATTAATGATTACTACTGGACTTGGCTCCGCCAGTCCCCAGGGAAAGGCCTGGAGTGGATTGGAAACATCTATAACAGTGGGAGCACCTACCAGAACCCGTCCCTCCAGAGTCGAGTTACCATGTCAGTGGACACGGCCAAGAACCACTTCTCCCTGAAGCTGACCTCTGTCACTGCCGCAGATACGGCCGTCTATTACTGTGCCAGAGATTTAGGCACTGCCAACAACTACTACTTCGGTATGGACGTCTGGGGCCTAGGGACCACGGTCACCGTCTCCTCA 338 5394 1698QVQLQESGPGRVKPSQTLSLTCTVSGVSVTINDYYWTWLRQSPGKGLEWIGNIYNSGSTYQNPSLQSRVTMSVDTAKNHFSLKLTSVTAADTAVYYCARDLGTANNYYFGMDVWGLGTTVTVSS 338 5395 1699 VSVTINDYYWT 338 5396 1700GTCTCCGTCACCATTAATGATTACTACTGGACT 338 5397 1701 NIYNSGSTYQNPSLQS 3385398 1702 AACATCTATAACAGTGGGAGCACCTACCAGAACCCGTCCCTCCAGAG T 338 53991703 ARDLGTANNYYFGMDV 338 5400 1704GCCAGAGATTTAGGCACTGCCAACAACTACTACTTCGGTATGGACGT C 338 5401 1705GATATTGTGCTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACTCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCACCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAATGGATCCAACAGGGTCACTGGCACCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCGTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCCGTACACTTTTGGCCAGGGGACCAAGGTGGAGATCAAA 338 5402 1706DIVLTQSPATLSLSPGERATLSCRASQSVSTYLAWYQQKPGQAPRLLIYNGSNRVTGTPARFSGSGSGTDFTLTISSVEPEDFAVYYCQQRSNWPPYTFG QGTKVEIK 338 54031707 RASQSVSTYLA 338 5404 1708 AGGGCCAGTCAGAGTGTTAGCACCTACTTAGCC 3385405 1709 NGSNRVT 338 5406 1710 AATGGATCCAACAGGGTCACT 338 5407 1711QQRSNWPPYT 338 5408 1712 CAGCAGCGTAGCAACTGGCCTCCGTACACT 339 5409 1713GAGGTGCAGCTGGTGGAGTCGGGCCCTGGACTGGTGAAGCCTTCAGAGACCCTGTCCCTCAGTTGCATTGTCTCTGGTGACTCCATCACCAGTAATGATTACTACTGGAGTTGGATCCGCCAGTCCCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATCACAGCGGGGCCACCTTCTACACTCCGTCCCTACGGAGTCGAGTGACCATATCGACAGACAGGTCCAAGAACCAGTTCTCCCTGAGACTGTCGTCTGTGACCGCCGCAGACACGGCCGTATATTATTGTGCCAGTGGACCTGTGGGGATGGCTACAAGCAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCA 339 5410 1714EVQLVESGPGLVKPSETLSLSCIVSGDSITSNDYYWSWIRQSPGKGLEWIGYIYHSGATFYTPSLRSRVTISTDRSKNQFSLRLSSVTAADTAVYYCASGPVGMATSNWFDPWGQGTLVTVSS 339 5411 1715 DSITSNDYYWS 339 5412 1716GACTCCATCACCAGTAATGATTACTACTGGAGT 339 5413 1717 YIYHSGATFYTPSLRS 3395414 1718 TACATCTATCACAGCGGGGCCACCTTCTACACTCCGTCCCTACGGAGT 339 5415 1719ASGPVGMATSNWFDP 339 5416 1720GCCAGTGGACCTGTGGGGATGGCTACAAGCAACTGGTTCGACCCC 339 5417 1721CAGCCTGTGCTGACTCAGCCACCCTCAGTGTCAGTCGCCCCGGGAAAGACGGCCACTCTTACGTGTGGGGGAGACATCATTAGAACTAACAGTGTGAACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTATTGATCATATATTATGATAGCGACCGGCCCTCAGGGATCCCTGGGCGATTCTCTGCCTCCAACTCTGGGAGCGCGGCCACCCTGACCATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGGTGTGGGACAGCAGTACTGATTATCACGTGGTTTTCGGCGGAGGGACCAAGCTCACCGTCCTA 339 5418 1722QPVLTQPPSVSVAPGKTATLTCGGDIIRTNSVNWYQQKPGQAPVLIIYYDSDRPSGIPGRFSASNSGSAATLTISRVEAGDEADYYCQVWDSSTDYHVVF GGGTKLTVL 339 54191723 GGDIIRTNSVN 339 5420 1724 GGGGGAGACATCATTAGAACTAACAGTGTGAAC 3395421 1725 YDSDRPS 339 5422 1726 TATGATAGCGACCGGCCCTCA 339 5423 1727QVWDSSTDYHVV 339 5424 1728 CAGGTGTGGGACAGCAGTACTGATTATCACGTGGTT 340 54251729 CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCATCTGGATACATCTTCACCGGTTATTTTATACACTGGGTGCGACAGGCCCCCGGACAAGGGCTTGAGTGGATGGGAGTAATCAATCCCAGAGGTGGAAGCACAAGCTACGCACAAAAGTTCCAGGGCAGAGTCGCTGTGTCCAGGGACACGTCCACGACTACAGTCTACATGGAGCTGAACAGCCTGAGATCTGAGGACACGGCCGTATATTACTGTGCGAGAGCCCCGAGCCACGATGAGTGGGTCGCAATTTCCCGAAATAACGATGTTGTGGGGTTCGACGCCTGGGGCCAGGGAACCCTGG TCACCGTCTCCTCA 340 54261730 QVQLVQSGAEVKKPGASVKVSCKASGYIFTGYFIHWVRQAPGQGLEWMGVINPRGGSTSYAQKFQGRVAVSRDTSTTTVYMELNSLRSEDTAVYYCARAPSHDEWVAISRNNDVVGFDAWGQGTLVTVSS 340 5427 1731 YIFTGYFIH 340 5428 1732TACATCTTCACCGGTTATTTTATACAC 340 5429 1733 VINPRGGSTSYAQKFQG 340 54301734 GTAATCAATCCCAGAGGTGGAAGCACAAGCTACGCACAAAAGTTCCA GGGC 340 5431 1735ARAPSHDEWVAISRNNDVVGFDA 340 5432 1736GCGAGAGCCCCGAGCCACGATGAGTGGGTCGCAATTTCCCGAAATAA CGATGTTGTGGGGTTCGACGCC340 5433 1737 CAGTCTGTCCTGACTCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGGGCAGCTCCAACATCGGGGCAGATTATGACGTACACTGGTACCAGCAGCCTCCAGGAACAGCCCCCAAACTCCTCATATTTGCTAACAACAATCGACCCTCAGGGGTCCCTGGCCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGCCTGAGTGCTTGGGTGTTCGGCGGGGGGACCAAGCTGACCGTCCT A 340 5434 1738QSVLTQPPSVSGAPGQRVTISCTGGSSNIGADYDVHWYQQPPGTAPKLLIFANNNRPSGVPGRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSAW VFGGGTKLTVL 340 54351739 TGGSSNIGADYDVH 340 5436 1740ACTGGGGGCAGCTCCAACATCGGGGCAGATTATGACGTACAC 340 5437 1741 ANNNRPS 3405438 1742 GCTAACAACAATCGACCCTCA 340 5439 1743 QSYDSSLSAWV 340 5440 1744CAGTCCTATGACAGCAGCCTGAGTGCTTGGGTG 341 5441 1745GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCCTCAGTAGTTATGCCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGTCTGGAGTGGGTCTCATCCATTAGTGCTGGAAGTAGTTACATCGACTACGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCTCTGTATCTGCAAATGAACAACCTGAGAGCCGAGGACACGGCTCTGTATTACTGTGCGAGAGAAGTTTTACCAGCAACCGCTATAGGAGGCGCCTGGCTCGACCCCTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA 341 5442 1746EVQLVESGGGLVKPGGSLRLSCAASGFTLSSYAMNWVRQAPGKGLEWVSSISAGSSYIDYADSVKGRFTISRDNAKNSLYLQMNNLRAEDTALYYCAREVLPATAIGGAWLDPWGQGTLVTVSS 341 5443 1747 FTLSSYAMN 341 5444 1748TTCACCCTCAGTAGTTATGCCATGAAC 341 5445 1749 SISAGSSYIDYADSVKG 341 54461750 TCCATTAGTGCTGGAAGTAGTTACATCGACTACGCAGACTCAGTGAA GGGC 341 5447 1751AREVLPATAIGGAWLDP 341 5448 1752GCGAGAGAAGTTTTACCAGCAACCGCTATAGGAGGCGCCTGGCTCGA CCCC 341 5449 1753CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGACGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCTGGATATGATGTCCACTGGTACCGGCAGCTTCCAGGAACAGCCCCCAAACTCCTCATCTATTCTAACAACAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGACACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGGGGATGAGGCTGATTATTACTGCCAGTCCTATGACATCAGCCTGAGTGCCTCTTATGTCTTCGGAACTGGGACCAAGGTCACCGTC CTA 341 5450 1754QSVLTQPPSVSGAPGQTVTISCTGSSSNIGAGYDVHWYRQLPGTAPKLLIYSNNNRPSGVPDRFSGSKSDTSASLAITGLQAGDEADYYCQSYDISLSAS YVFGTGTKVTVL 341 54511755 TGSSSNIGAGYDVH 341 5452 1756ACTGGGAGCAGCTCCAACATCGGGGCTGGATATGATGTCCAC 341 5453 1757 SNNNRPS 3415454 1758 TCTAACAACAATCGGCCCTCA 341 5455 1759 QSYDISLSASYV 341 5456 1760CAGTCCTATGACATCAGCCTGAGTGCCTCTTATGTC 342 5457 1761CAGGTCCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAACTATGGTTTCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCCTCACTCACAATGGTTACACAAACTATGCACAGAAGTTCCAGGACAGAGTCACCATGAAGACAGACACATCCACGAGCACAGTCTACATGGAGCTGAGGAGCCTGAGATCTGTCGACACGGCCGTGTATTACTGTGCGAGAATTGGCCATGTTACAGCCGTGGCTGGTGCCCCTCCTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 342 5458 1762QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGFSWVRQAPGQGLEWMGWILTHNGYTNYAQKFQDRVTMKTDTSTSTVYMELRSLRSVDTAVYYCARIGHVTAVAGAPPDYWGQGTLVTVSS 342 5459 1763 YTFTNYGFS 342 5460 1764TACACCTTTACCAACTATGGTTTCAGC 342 5461 1765 WILTHNGYTNYAQKFQD 342 54621766 TGGATCCTCACTCACAATGGTTACACAAACTATGCACAGAAGTTCCA GGAC 342 5463 1767ARIGHVTAVAGAPPDY 342 5464 1768GCGAGAATTGGCCATGTTACAGCCGTGGCTGGTGCCCCTCCTGACTAC 342 5465 1769CAGCCTGTGCTGACTCAGCCTGCCTCCGTGTCTGGGTATCAAGGACAGTCGATCACCATCTCCTGCAGTGGAACCAGCAGTGATGTTGGGACTTATAACCTTGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCGAACTCATGATTTATGAGGGCAGTAAGCGGCCCTCAGGGGTTTCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACAATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCTGCTCATATGTAGCTGGTAGTACTTCAGTATTCGGCGGAGGGACCAAGCTCACCGTCCTA 342 5466 1770QPVLTQPASVSGYQGQSITISCSGTSSDVGTYNLVSWYQQHPGKAPELMIYEGSKRPSGVSDRFSGSKSGNTASLTISGLQAEDEADYYCCSYVAGSTSV FGGGTKLTVL 342 54671771 SGTSSDVGTYNLVS 342 5468 1772AGTGGAACCAGCAGTGATGTTGGGACTTATAACCTTGTCTCC 342 5469 1773 EGSKRPS 3425470 1774 GAGGGCAGTAAGCGGCCCTCA 342 5471 1775 CSYVAGSTSV 342 5472 1776TGCTCATATGTAGCTGGTAGTACTTCAGTA 343 5473 1777GAGGTGCAGCTGGTGGAGTCGGGCCCTGGACTGGTGAAGCCTTCAGAGACCCTGTCCCTCAGTTGCATTGTCTCTGGTGGCTCCATCACCAGTGGTGATTACTACTGGAGTTGGCTCCGCCAGTCCCCAGGGAAGGGCCTGGAGTGGATTGGGTACATATATCACAGCGGGGCCACCTTCTACACCCCGTCCCTACGGAGTCGAGTGACCATTTCGACAGACACCTCCAAGAACCAATTCTCCCTGAGACTGTCGTCTGTGACCGCCGCAGACACGGCCGTTTATTATTGTGCCAGTGGACCTGTCGGGATGGCTACAAGCAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 343 5474 1778EVQLVESGPGLVKPSETLSLSCIVSGGSITSGDYYWSWLRQSPGKGLEWIGYIYHSGATFYTPSLRSRVTISTDTSKNQFSLRLSSVTAADTAVYYCASGPVGMATSNWFDPWGQGTLVTVSS 343 5475 1779 GSITSGDYYWS 343 5476 1780GGCTCCATCACCAGTGGTGATTACTACTGGAGT 343 5477 1781 YIYHSGATFYTPSLRS 3435478 1782 TACATATATCACAGCGGGGCCACCTTCTACACCCCGTCCCTACGGAGT 343 5479 1783ASGPVGMATSNWFDP 343 5480 1784GCCAGTGGACCTGTCGGGATGGCTACAAGCAACTGGTTCGACCCC 343 5481 1785TCCTATGAGCTGACACAGCCACCCTCAGTATCAGTCGCCCCGGGAAAGACGGCCACCATTACGTGTGGGGGAGACATCATTAGAACTAACAGTGTGAACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTCTATTGCTCATCTATTATGATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGCCTCCAACTCTGGGAACACGGCCACCCTGACCATCAGCAGGGTCGAGGCCGGGGATGAGGCCGACTATTACTGTCAGGTGTGGGACAGTGGTACTGATTATCACGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTCCAA 343 5482 1786SYELTQPPSVSVAPGKTATITCGGDIIRTNSVNWYQQKPGQAPLLLIYYDSDRPSGIPERFSASNSGNTATLTISRVEAGDEADYYCQVWDSGTDYHVVF GGGTKLTVQ 343 54831787 GGDIIRTNSVN 343 5484 1788 GGGGGAGACATCATTAGAACTAACAGTGTGAAC 3435485 1789 YDSDRPS 343 5486 1790 TATGATAGCGACCGGCCCTCA 343 5487 1791QVWDSGTDYHVV 343 5488 1792 CAGGTGTGGGACAGTGGTACTGATTATCACGTGGTT 344 54891793 CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAGGCCTGGGGCCTCAGTGAAAGTCTCCTGCAAGGCTTCTGAATACGCCTTCACCGCCCACTATCTTCACTGGGTGCGACAGGCCCCTGATCAAGGACTTGAGTGGATGGGATGGATCAGCCCTAAAAGTGGTGGCACCAACTATGCACAGAAGTTTCACGGCAGGGTCAGCATGACCAGTGACACGTCCATCAGTACAGTCTATATGGAACTGAGCAGCCTGACATCTGACGACACGGCCGTCTATTACTGTGCGAGAAGCAGTCTGGTGGGAGCAAGCCCCAACTTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 344 5490 1794QVQLVQSGAEVKRPGASVKVSCKASEYAFTAHYLHWVRQAPDQGLEWMGWISPKSGGTNYAQKFHGRVSMTSDTSISTVYMELSSLTSDDTAVYYCARSSLVGASPNFDFWGQGTLVTVSS 344 5491 1795 YAFTAHYLH 344 5492 1796TACGCCTTCACCGCCCACTATCTTCAC 344 5493 1797 WISPKSGGTNYAQKFHG 344 54941798 TGGATCAGCCCTAAAAGTGGTGGCACCAACTATGCACAGAAGTTTCA CGGC 344 5495 1799ARSSLVGASPNFDF 344 5496 1800 GCGAGAAGCAGTCTGGTGGGAGCAAGCCCCAACTTTGACTTC344 5497 1801 CAGTCTGTGGTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAACTCCCAGGATCTACCCCCAAAGTCCTCATTTACGACAATAATCAGCGACCCTCAGGGATTCCTGACCGTTTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGCCATCAGCGGACTCCAGACTGGCGACGAGGCCGTCTATTATTGCGGAACATGGGATGCCAGCCTGAGTGCTGCAATGGTTTTCGGCGGGGGGACCAAGCTCACCGTCCT A 344 5498 1802QSVVTQPPSVSAAPGQRVTISCSGSSSNIGNNYVSWYQQLPGSTPKVLIYDNNQRPSGIPDRFSGSKSGTSATLAISGLQTGDEAVYYCGTWDASLSAA MVFGGGTKLTVL 344 54991803 SGSSSNIGNNYVS 344 5500 1804 TCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCC344 5501 1805 DNNQRPS 344 5502 1806 GACAATAATCAGCGACCCTCA 344 5503 1807GTWDASLSAAMV 344 5504 1808 GGAACATGGGATGCCAGCCTGAGTGCTGCAATGGTT 345 55051809 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTAACCTGCGCTGTCTCTGGTGGGTACTTCATTAATGACAACTGGAGCTGGATCCGCCAGTCCCCAGGGAAGGGGCTGGAGTGGATTGGAGAAATTAGTCATAGTGGAAGCACCAACTACAATCCGTCCCTCAAGAGTCGACTCACCATATCAGTTGACACGTCCAGGCAGCAGTTTTCCCTGAAATTGAGCTCTGTGACCGCCGCGGACAGTGGTGTTTACTACTGTGCGCGAGTCCACCCGTCGTATGACTTTGGCTGGCGCTTCTTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCA 345 5506 1810QVQLQQWGAGLLKPSETLSLTCAVSGGYFINDNWSWIRQSPGKGLEWIGEISHSGSTNYNPSLKSRLTISVDTSRQQFSLKLSSVTAADSGVYYCARVHPSYDFGWRFFDFWGQGTLVTVSS 345 5507 1811 GYFINDNWS 345 5508 1812GGGTACTTCATTAATGACAACTGGAGC 345 5509 1813 EISHSGSTNYNPSLKS 345 5510 1814GAAATTAGTCATAGTGGAAGCACCAACTACAATCCGTCCCTCAAGAG T 345 5511 1815ARVHPSYDFGWRFFDF 345 5512 1816GCGCGAGTCCACCCGTCGTATGACTTTGGCTGGCGCTTCTTTGACTTC 345 5513 1817GAAACGACACTCACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGATACAGCCACCCTCTCCTGCAGGGCCAGTCAGACTATTAGTTCCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGCCTCCCAGTCTCCTCATCTATGGAGCATCCAACAGGGCCACTGGTATCCCAGACAGGTTTCGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATGCATACTGGCCTCCGTACACTTTTGGCCAGGGGACCAAGGTGGAGATCAAA 345 5514 1818ETTLTQSPATLSVSPGDTATLSCRASQTISSNLAWYQQKPGQPPSLLIYGASNRATGIPDRFRGSGSGTEFTLTISSLQSEDFAVYYCQQYAYWPPYTFGQ GTKVEIK 345 5515 1819RASQTISSNLA 345 5516 1820 AGGGCCAGTCAGACTATTAGTTCCAACTTAGCC 345 55171821 GASNRAT 345 5518 1822 GGAGCATCCAACAGGGCCACT 345 5519 1823QQYAYWPPYT 345 5520 1824 CAGCAGTATGCATACTGGCCTCCGTACACT 346 5521 1825GAGGTGCAGCTGTTGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCGGGTGGCTCCATCAACAGTATTGATTATTATTGGAGCTGGATCCGCCAGCCCCCAGGGAAGGGCCTGGAGTGGATTGGCTACATTTATCACAGTGGGAGCACCCACTACAGACCATCCCTCAAGAGTCGAGTAACGATATCATTAGACAAGGCCAAGAACGAGTTCTCGCTGAGTCTGACCTCTGTGACTGCCGCAGACACGGCCGTGTATTTCTGTGCCAGTGGCCCCGTCGGGATGGCAACAAGCAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 346 5522 1826EVQLLESGPGLVKPSQTLSLTCTVSGGSINSIDYYWSWIRQPPGKGLEWIGYIYHSGSTHYRPSLKSRVTISLDKAKNEFSLSLTSVTAADTAVYFCASGPVGMATSNWFDPWGQGTLVTVSS 346 5523 1827 GSINSIDYYWS 346 5524 1828GGCTCCATCAACAGTATTGATTATTATTGGAGC 346 5525 1829 YIYHSGSTHYRPSLKS 3465526 1830 TACATTTATCACAGTGGGAGCACCCACTACAGACCATCCCTCAAGAG T 346 55271831 ASGPVGMATSNWFDP 346 5528 1832GCCAGTGGCCCCGTCGGGATGGCAACAAGCAACTGGTTCGACCCC 346 5529 1833CAGCCTGTGCTGACTCAGCCACCCTCAGTGTCAGTGACCCCAGGAGAGACGGCCAGGCTTCCCTGTGAGGGAGACATCGTTGTCACTAACAGTGTCCACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTTTTGGTCGTCTATTATGATAGCGACCGGGCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAATTCTGGGAACACGGCCACCCTGAGCATCAGCAGGGTCGAAGCCGGGGATGAGGCCGACTACTATTGTCAGGTGTGGGATAGTAGTACTGATCATCATGTGGTGTTCGGCGGTGGGACCAAGCTCACCGTCCTA 346 5530 1834QPVLTQPPSVSVTPGETARLPCEGDIVVTNSVHWYQQKPGQAPVLVVYYDSDRASGIPERFSGSNSGNTATLSISRVEAGDEADYYCQVWDSSTDHHV VFGGGTKLTVL 346 55311835 EGDIVVTNSVH 346 5532 1836 GAGGGAGACATCGTTGTCACTAACAGTGTCCAC 3465533 1837 YDSDRAS 346 5534 1838 TATGATAGCGACCGGGCCTCA 346 5535 1839QVWDSSTDHHVV 346 5536 1840 CAGGTGTGGGATAGTAGTACTGATCATCATGTGGTG 347 55371841 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCAGATTCAGCAGCGACGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGAATCATCCCTATCCGTGGGACACCAACCTACGCACAGAAGTTCCAGGGCAGAGTCACGATTATCGCGGACGAATCCACGACTACATCCTACATGGAGATGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGACCGAATTACGATATTTTGACTGGTTATAATGATGCTTTTGATATTTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA 347 5538 1842QVQLVQSGAEVKKPGSSVKVSCKASGGRFSSDAISWVRQAPGQGLEWMGGIIPIRGTPTYAQKFQGRVTIIADESTTTSYMEMSSLRSEDTAVYYCARPNYDILTGYNDAFDIWGQGTMVTVSS 347 5539 1843 GRFSSDAIS 347 5540 1844GGCAGATTCAGCAGCGACGCTATCAGC 347 5541 1845 GIIPIRGTPTYAQKFQG 347 55421846 GGAATCATCCCTATCCGTGGGACACCAACCTACGCACAGAAGTTCCA GGGC 347 5543 1847ARPNYDILTGYNDAFDI 347 5544 1848GCGAGACCGAATTACGATATTTTGACTGGTTATAATGATGCTTTTGAT ATT 347 5545 1849CAGTCTGTGTTGACGCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGCAGTGATGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGTCCCCAGACTCATGATTTACGATGTCAGTAAGCGGCCCTCAGGGGCCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCTGCTCATATGCAGGCGGCCTTTATGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA 347 5546 1850QSVLTQPRSVSGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKVPRLMIYDVSKRPSGAPDRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGGLYV FGTGTKLTVL 347 55471851 TGTSSDVGGYNYVS 347 5548 1852ACTGGAACCAGCAGTGATGTTGGTGGTTATAACTATGTCTCC 347 5549 1853 DVSKRPS 3475550 1854 GATGTCAGTAAGCGGCCCTCA 347 5551 1855 CSYAGGLYV 347 5552 1856TGCTCATATGCAGGCGGCCTTTATGTC 348 5553 1857GAGGTGCAGCTGGTGGAGTCCGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCACTTATGATATCAACTGGGTGCGACAGGCCACTGGACGGGGGCTTGAGTGGATGGGATGGATGACCCCTGATAGTGGTAGCACAGGCTATCCACAGAACTTCCAGGGCAGAGTCACCATGACCAGGAACACCTCCATAAGCACAGCCTACATGGAGTTGAGCAACCTGAGATCTGAGGACACGGCCGTATATTACTGTGTGCAAATGGACCATTGTAGAAGTACCAGCTGCTCTGAGGGGAACTGGTTCGACACCTGGGGCCAGGGAACCCTGGTCACCGTCTCCT CA 348 5554 1858EVQLVESGAEVKKPGASVKVSCKASGYTFTTYDINWVRQATGRGLEWMGWMTPDSGSTGYPQNFQGRVTMTRNTSISTAYMELSNLRSEDTAVYYCVQMDHCRSTSCSEGNWFDTWGQGTLVTVSS 348 5555 1859 YTFTTYDIN 348 5556 1860TACACCTTCACCACTTATGATATCAAC 348 5557 1861 WMTPDSGSTGYPQNFQG 348 55581862 TGGATGACCCCTGATAGTGGTAGCACAGGCTATCCACAGAACTTCCA GGGC 348 5559 1863VQMDHCRSTSCSEGNWFDT 348 5560 1864GTGCAAATGGACCATTGTAGAAGTACCAGCTGCTCTGAGGGGAACTG GTTCGACACC 348 5561 1865CAGCCTGGGCTGACTCAGCCACCCTCGGTGTCTGCAGCCCCCAGGCAGAGGGTCACCATCTCCTGTTCTGGAAGCAGCTCCAACATCGGAACTAATGCTGTAAACTGGTACCAGCAGCTCCCAGGAAAGGCTCCCAAACTCCTCATCTATTCTGATAATCTGATGCCCTCAGGGGTCTCTGCCCGATTCTCTGGCTCCAAGTCTGGCACCTCGGCCTCCCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAATGTTTGGGTGTTCGGCGGGGGGACCAAGCTCACCGTCCTA 348 5562 1866QPGLTQPPSVSAAPRQRVTISCSGSSSNIGTNAVNWYQQLPGKAPKLLIYSDNLMPSGVSARFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNVW VFGGGTKLTVL 348 55631867 SGSSSNIGTNAVN 348 5564 1868 TCTGGAAGCAGCTCCAACATCGGAACTAATGCTGTAAAC348 5565 1869 SDNLMPS 348 5566 1870 TCTGATAATCTGATGCCCTCA 348 5567 1871AAWDDSLNVWV 348 5568 1872 GCAGCATGGGATGACAGCCTGAATGTTTGGGTG 349 55691873 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTGAAGCCAGGGCGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCAACTTCGGTGATTATGCTATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTAGGTTTCATTAGAAGCAAAACTTATCGTGAGACAAGAGAATACGCCGCGTCTGTGAAAGGCAGATTCACCATGTCAAGAGATGATTTCAACAGGATCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCATGTATTATTGTACGAGACAAGACGATTTTTGGAGTGGTCATCCCTACTACTTTGAGTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 349 5570 1874EVQLVESGGGLVKPGRSLRLSCTASGFNFGDYAMSWFRQAPGKGLEWVGFIRSKTYRETREYAASVKGRFTMSRDDFNRIAYLQMNSLKTEDTAMYYCTRQDDFWSGHPYYFEYWGQGTLVTVSS 349 5571 1875 FNFGDYAMS 349 5572 1876TTCAACTTCGGTGATTATGCTATGAGC 349 5573 1877 FIRSKTYRETREYAASVKG 349 55741878 TTCATTAGAAGCAAAACTTATCGTGAGACAAGAGAATACGCCGCGTC TGTGAAAGGC 349 55751879 TRQDDFWSGHPYYFEY 349 5576 1880ACGAGACAAGACGATTTTTGGAGTGGTCATCCCTACTACTTTGAGTAC 349 5577 1881CAGCCTGTGCTGACTCAGCCCCCCTCCGCGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAACAGTGACGTGGGTAGTTATAACTATGTCTCCTGGTACCAACATCACCCAGGCAAAGCCCCCAAACTCATCATTTATGACGTCGCTAAGCGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCAGTAACGATTTGGGGGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA 349 5578 1882QPVLTQPPSASGSPGQSVTISCTGTNSDVGSYNYVSWYQHHPGKAPKLIIYDVAKRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGSNDL GVFGTGTKLTVL 349 55791883 TGTNSDVGSYNYVS 349 5580 1884ACTGGAACCAACAGTGACGTGGGTAGTTATAACTATGTCTCC 349 5581 1885 DVAKRPS 3495582 1886 GACGTCGCTAAGCGGCCCTCA 349 5583 1887 SSYAGSNDLGV 349 5584 1888AGCTCATATGCAGGCAGTAACGATTTGGGGGTC 350 5585 1889GAGGTGCAGCTGGTGGAGTCCGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTGTCTGGTGGCTCCGTCAGTGGTCACTACTGGAGCTGGATTCGGCAGTTCCCAGGGAAGGAACTGGAATGGATTGGTCATATCTATTATATTGGGACGACCAACTACAACCCCTCCCTCAAGAGTCGAGTCATCATATCGCTAGACACGTCCAAGAATCAGCTCTCCCTGAAGCTGAGTTCTGTGACCGCTGCGGACACTGCCGTTTATTATTGTGCCAGACAGTTCGGCTATGATAAAAATACTTTAAGTCGGCTTGACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 350 5586 1890EVQLVESGPGLVKPSETLSLTCTVSGGSVSGHYWSWIRQFPGKELEWIGHIYYIGTTNYNPSLKSRVIISLDTSKNQLSLKLSSVTAADTAVYYCARQFGYDKNTLSRLDFDYWGQGTLVTVSS 350 5587 1891 GSVSGHYWS 350 5588 1892GGCTCCGTCAGTGGTCACTACTGGAGC 350 5589 1893 HIYYIGTTNYNPSLKS 350 5590 1894CATATCTATTATATTGGGACGACCAACTACAACCCCTCCCTCAAGAGT 350 5591 1895ARQFGYDKNTLSRLDFDY 350 5592 1896GCCAGACAGTTCGGCTATGATAAAAATACTTTAAGTCGGCTTGACTTT GACTAC 350 5593 1897GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAAGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAACAGAGACCAGGGAAAGCCCCTAAGCTCCTGATCTATTCTGCATTCAGTTTACATAGTGGTGTCCCATCAAGGTTCAGTGGCAGTGGATCTGAGACAGAGTTCACTCTCACCATCAGCAGTCTGCAACCTGACGATTTTGCAACTTATTACTGTCAACAGAGTTACAGTATTCCCTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 350 5594 1898DIQMTQSPSSLSASVRDRVTITCRASQSISSYLNWYQQRPGKAPKLLIYSAFSLHSGVPSRFSGSGSETEFTLTISSLQPDDFATYYCQQSYSIPWTFGQGTK VEIK 350 5595 1899RASQSISSYLN 350 5596 1900 CGGGCAAGTCAGAGCATTAGCAGCTATTTAAAT 350 55971901 SAFSLHS 350 5598 1902 TCTGCATTCAGTTTACATAGT 350 5599 1903 QQSYSIPWT350 5600 1904 CAACAGAGTTACAGTATTCCCTGGACG 351 5601 1905CAGGTGCAGCTGCAGGAGTCCGGCCCGGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCAGTGTCTCTGGTGGCTCCATCACCAATGTTAATTACTACTGGGGCTGGATCCGCCAGCCCCCCGGGAAGGGCCTGGAGTGGATTGGGAGTATCTATTATAATGGAAACACCTACTACAACCCGTCCCTCCAGAGTCGAGTCACCATGTCCGTGGACACGTCCAAGAACCACTTCTCCCTGAGGCTGACGTCTGTGACCGCCGCAGACACGGCTGTATATTTTTGTGCGAGAGAGGGGCCTAATTGGGAATTGTTGAATGCTTTCGATATCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 351 5602 1906QVQLQESGPGLVKPSETLSLTCSVSGGSITNVNYYWGWIRQPPGKGLEWIGSIYYNGNTYYNPSLQSRVTMSVDTSKNHFSLRLTSVTAADTAVYFCAREGPNWELLNAFDIWGQGTTVTVSS 351 5603 1907 GSITNVNYYWG 351 5604 1908GGCTCCATCACCAATGTTAATTACTACTGGGGC 351 5605 1909 SIYYNGNTYYNPSLQS 3515606 1910 AGTATCTATTATAATGGAAACACCTACTACAACCCGTCCCTCCAGAGT 351 5607 1911AREGPNWELLNAFDI 351 5608 1912GCGAGAGAGGGGCCTAATTGGGAATTGTTGAATGCTTTCGATATC 351 5609 1913TCCTATGAGCTGACTCAGCCACCCTCGGTGTCAGTGGCCCCAGGACAGACGGCCAGGATTACCTGTGGGGGAAACAACATTGGAAGTAAAAATGTGCACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTCTTGGTCGTCTATGAGGATACCCACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACCATCAGTAGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGGTGTGGGATACTAGTAGTGATCATGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTC 351 5610 1914SYELTQPPSVSVAPGQTARITCGGNNIGSKNVHWYQQKPGQAPVLVVYEDTHRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDTSSDHVVF GGGTKLTVL 351 56111915 GGNNIGSKNVH 351 5612 1916 GGGGGAAACAACATTGGAAGTAAAAATGTGCAC 3515613 1917 EDTHRPS 351 5614 1918 GAGGATACCCACCGGCCCTCA 351 5615 1919QVWDTSSDHVV 351 5616 1920 CAGGTGTGGGATACTAGTAGTGATCATGTGGTA 352 56171921 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGACTTCTGGTTACACCTTTAGTCATTTCGGTGTCACCTGGATACGACAGGCCCCAGGACAAGGGCTTGAGTGGCTGGGATGGATCAGCGCTTACAATGGTAACACAGACTCTGCAGACAAACTGCAGGGCAGACTCACCATGACGACAGACACATCCACGAACACCGCCTACATGGAGTTGAGGAGCCTCAGATCTGACGACACGGCCGTCTATTACTGTGCGAGAGATCCCCCCGCATCAGCTGCTGCCATGCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 352 5618 1922QVQLVQSGAEVKKPGASVKVSCKTSGYTFSHFGVTWIRQAPGQGLEWLGWISAYNGNTDSADKLQGRLTMTTDTSTNTAYMELRSLRSDDTAVYYCARDPPASAAAMLDYWGQGTLVTVSS 352 5619 1923 YTFSHFGVT 352 5620 1924TACACCTTTAGTCATTTCGGTGTCACC 352 5621 1925 WISAYNGNTDSADKLQG 352 56221926 TGGATCAGCGCTTACAATGGTAACACAGACTCTGCAGACAAACTGCA GGGC 352 5623 1927ARDPPASAAAMLDY 352 5624 1928 GCGAGAGATCCCCCCGCATCAGCTGCTGCCATGCTTGACTAC352 5625 1929 GACATCCAGATGACCCAGTCTCCACTCTCCCTGGCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAGGCCTCGAATACACTGATGGAAACACCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTCATTTATAAGGTTTCTAATCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGCGGGGCAGGCACTGATTTCACACTGAGAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGTACACACGGGCGGGGAATCTCTTTCGGTCCTGGGACCAAAGTGGA TATCAAA 352 5626 1930DIQMTQSPLSLAVTLGQPASISCRSSQGLEYTDGNTYLSWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGAGTDFTLRISRVEAEDVGVYYCMQGTHG RGISFGPGTKVDIK 3525627 1931 RSSQGLEYTDGNTYLS 352 5628 1932AGGTCTAGTCAAGGCCTCGAATACACTGATGGAAACACCTACTTGAG T 352 5629 1933 KVSNRDS352 5630 1934 AAGGTTTCTAATCGGGACTCT 352 5631 1935 MQGTHGRGIS 352 56321936 ATGCAAGGTACACACGGGCGGGGAATCTCT 353 5633 1937CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAGGGTCTCCTGCAAGGCCTCTGGATACACCTTCACCGACTACTTTATGAACTGGGTGCGACAGGCCCCTGGAGGGGGCCTTGAGTGGATGGGGTGGATCAATCCTCTCAGTGGAGTCACAAAATATGCACAGCAGTTTCAGGGCAGTGTCACCATGACCACTGACACGTCCATCACCACAGGCTACATGGAGCTGAGGAGCCTGAGAGTTGACGACACGGCCGTCTATTATTGTGCGAGCCAGTCTTCCCCTTACACCCCGGGCGCCATGGGCGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 353 5634 1938QVQLVQSGAEVKKPGASVRVSCKASGYTFTDYFMNWVRQAPGGGLEWMGWINPLSGVTKYAQQFQGSVTMTTDTSITTGYMELRSLRVDDTAVYYCASQSSPYTPGAMGVWGQGTTVTVSS 353 5635 1939 YTFTDYFMN 353 5636 1940TACACCTTCACCGACTACTTTATGAAC 353 5637 1941 WINPLSGVTKYAQQFQG 353 56381942 TGGATCAATCCTCTCAGTGGAGTCACAAAATATGCACAGCAGTTTCA GGGC 353 5639 1943ASQSSPYTPGAMGV 353 5640 1944 GCGAGCCAGTCTTCCCCTTACACCCCGGGCGCCATGGGCGTC353 5641 1945 GACATCCGGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGACAAGTCAGAGCGTTAGCGGCTATTTAAGTTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCGGCATCCAATTTGTACAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACTGAATTCCGGTGCCCTATTCACTTTCGGCCCTGGGACCAAGGTGGAAATCAAA 353 5642 1946DIRMTQSPSSLSASVGDRVTITCRTSQSVSGYLSWYQQKPGKAPKLLIYAASNLYSGVPSRFSGSGSGTDFTLTITSLQPEDFATYFCQLNSGALFTFGPG TKVEIK 353 5643 1947RTSQSVSGYLS 353 5644 1948 CGGACAAGTCAGAGCGTTAGCGGCTATTTAAGT 353 56451949 AASNLYS 353 5646 1950 GCGGCATCCAATTTGTACAGT 353 5647 1951 QLNSGALFT353 5648 1952 CAACTGAATTCCGGTGCCCTATTCACT 354 5649 1953GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGAGTCCGTGAAACTCTCCTGCGCAGCGTCTGGATTCACCATCACTGACTCCTACATGGCCTGGATCCGCCAGTCTCCAGGGAAGGGGCTGGAGTGGCTTGCTTACATTAGTAGTACTAGTCTTTTCACAGACTACACAGACTCTGTGAAGGGCCGATTCATCATCACCAGAGACAATGCCGAGAACTCACTCTATCTGCAAATGACCAGCCTGACACCGGCAGACACGGGTGTCTATTTCTGTGCGAGGGCCAAAACATCCTACTACTTCTACGCTCTGGACGTCTGGGGCCCAGGCACCCTGGTCACCGTCTCCTCA 354 5650 1954EVQLVESGGGLVKPGESVKLSCAASGFTITDSYMAWIRQSPGKGLEWLAYISSTSLFTDYTDSVKGRFIITRDNAENSLYLQMTSLTPADTGVYFCARAKTSYYFYALDVWGPGTLVTVSS 354 5651 1955 FTITDSYMA 354 5652 1956TTCACCATCACTGACTCCTACATGGCC 354 5653 1957 YISSTSLFTDYTDSVKG 354 56541958 TACATTAGTAGTACTAGTCTTTTCACAGACTACACAGACTCTGTGAAG GGC 354 5655 1959ARAKTSYYFYALDV 354 5656 1960 GCGAGGGCCAAAACATCCTACTACTTCTACGCTCTGGACGTC354 5657 1961 GAAACGACACTCACGCAGTCTCCAGGCACGCTGTCTTTGTCTCCGGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACAACAACTATCTAGCCTGGTTCCAGCACAAACCTGGCCAGGCTCCCAGACTCCTCATCTATAATGCATCCAACAGGGCCGCTGGCATCCCAGACAGGTTCAGTGGTAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAAACTGGAGCCTGGAGATTCTGCAGTGTATTACTGTCAGCGATATGGGAACTCTTGGCCGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 354 5658 1962ETTLTQSPGTLSLSPGERATLSCRASQSVNNNYLAWFQHKPGQAPRLLIYNASNRAAGIPDRFSGSGSGTDFTLTISKLEPGDSAVYYCQRYGNSWPFGQ GTKVEIK 354 5659 1963RASQSVNNNYLA 354 5660 1964 AGGGCCAGTCAGAGTGTTAACAACAACTATCTAGCC 354 56611965 NASNRAA 354 5662 1966 AATGCATCCAACAGGGCCGCT 354 5663 1967 QRYGNSWP354 5664 1968 CAGCGATATGGGAACTCTTGGCCG 355 5665 1969CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGTCAGTCTCCCATGAGCTGGGTCCGCCAGGCTCCTGGGAAGGGGCTGGAGTGGGTCTCCGGTATTAGTACTGGAGGGACCAATACATACTACGCAGACTCCGTGAAGGGCCGCTTCACCATCTCCAGAGACAATTCCAAGAACACGTTGTATCTGCAAATGACCAGCCTGAGAGTCGGGGACACGGCCGTGTATTACTGTGCGAAAGAGAGTTTAGACTTTGGTTCAGGGAGCTACAACTGGTTCGACACCTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA 355 5666 1970QVQLVQSGGGLVQPGGSLRLSCAASGFTFSQSPMSWVRQAPGKGLEWVSGISTGGTNTYYADSVKGRFTISRDNSKNTLYLQMTSLRVGDTAVYYCAKESLDFGSGSYNWFDTWGQGTLVTVSS 355 5667 1971 FTFSQSPMS 355 5668 1972TTCACCTTTAGTCAGTCTCCCATGAGC 355 5669 1973 GISTGGTNTYYADSVKG 355 56701974 GGTATTAGTACTGGAGGGACCAATACATACTACGCAGACTCCGTGAA GGGC 355 5671 1975AKESLDFGSGSYNWFDT 355 5672 1976GCGAAAGAGAGTTTAGACTTTGGTTCAGGGAGCTACAACTGGTTCGA CACC 355 5673 1977GAAATTGTATTGACGCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGGTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAGACCAGGACAGCCTCCTAGGCTGCTCATTTCCTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCACTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCACCAATATTATGATACCCACACTTTTGGCCAGGGGACCAAAGTGGATATC AAA 355 5674 1978EIVLTQSPDSLAVSLGERATINCKSSQSVLYRSNNKNYLAWYQQRPGQPPRLLISWASTRESGVPDRFTGSGSGTDFTLTISSLQAEDVAVYYCHQYYDT HTFGQGTKVDIK 355 56751979 KSSQSVLYRSNNKNYLA 355 5676 1980AAGTCCAGCCAGAGTGTTTTATACAGGTCCAACAATAAGAACTACTT AGCT 355 5677 1981WASTRES 355 5678 1982 TGGGCATCTACCCGGGAATCC 355 5679 1983 HQYYDTHT 3555680 1984 CACCAATATTATGATACCCACACT 356 5681 1985GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTCAGCTTCAGTGCCTATGGCATGCACTGGGTTCGCCAGGTTCCAACCAAGGGGCTGGAGTGGGTGGCTGTTATATCATATGATGGAAGAGATATATACTATACAGACTCCGTGAAGGGCCGATTCACCATTTCCAGAGACAATTCCAAGAACATGTTGTATCTGCAAATGAACAGCCTGAGACCTGAGGACAGGGCTGTCTATTACTGTGCGAGAGATCCGTCCCTCGGTTATAATAATCACTACTTTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCA 356 5682 1986EVQLVESGGGVVQPGRSLRLSCVASGFSFSAYGMHWVRQVPTKGLEWVAVISYDGRDIYYTDSVKGRFTISRDNSKNMLYLQMNSLRPEDRAVYYCARDPSLGYNNHYFDYWGQGTLVTVSS 356 5683 1987 FSFSAYGMH 356 5684 1988TTCAGCTTCAGTGCCTATGGCATGCAC 356 5685 1989 VISYDGRDIYYTDSVKG 356 56861990 GTTATATCATATGATGGAAGAGATATATACTATACAGACTCCGTGAA GGGC 356 5687 1991ARDPSLGYNNHYFDY 356 5688 1992GCGAGAGATCCGTCCCTCGGTTATAATAATCACTACTTTGACTAT 356 5689 1993GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAACAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTACCGGCAACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGCTGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTTCTGTCAGCAGCGTAGCAACTGGCCTCCTATGTACAGTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 356 5690 1994EIVLTQSPATLSLSPGETATLSCRASQSVTGNLAWYQQKPGQAPRLLIYAASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQRSNWPPMYSFG QGTKLEIK 356 56911995 RASQSVTGNLA 356 5692 1996 AGGGCCAGTCAGAGTGTTACCGGCAACTTAGCC 3565693 1997 AASNRAT 356 5694 1998 GCTGCATCCAACAGGGCCACT 356 5695 1999QQRSNWPPMYS 356 5696 2000 CAGCAGCGTAGCAACTGGCCTCCTATGTACAGT 357 56972001 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGAGGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCCTCTGGAGGCACCTTCAGAGGCTACCATATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTCGAGTGGATGGGAGGGATCATCCATCTATTTGGGACAGTAAGCTACGCTCCGAAGTTCCAGGGCAGAGTCACGATCACCGCGGACGCATCCACGGGCACAGCCCATATGGAGTTGAGCAGCCTGACATCTGACGACACGGCCATATACTATTGTGCGAGAGATGCTTACGAAGTCTGGACGGGTTCTTATCTCCCCCCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 357 5698 2002QVQLVQSGAEVKRPGSSVKVSCKASGGTFRGYHISWVRQAPGQGLEWMGGIIHLFGTVSYAPKFQGRVTITADASTGTAHMELSSLTSDDTAIYYCARDAYEVWTGSYLPPFDYWGQGTLVTVSS 357 5699 2003 GTFRGYHIS 357 5700 2004GGCACCTTCAGAGGCTACCATATCAGC 357 5701 2005 GIIHLFGTVSYAPKFQG 357 57022006 GGGATCATCCATCTATTTGGGACAGTAAGCTACGCTCCGAAGTTCCAG GGC 357 5703 2007ARDAYEVWTGSYLPPFDY 357 5704 2008GCGAGAGATGCTTACGAAGTCTGGACGGGTTCTTATCTCCCCCCTTTT GACTAC 357 5705 2009GATATTGTGATGACTCAGACTCCAGGCACCCTGTCTTTGTCTCCCGGGGAAAGAGTCACCCTCTCCTGCAGGGCCAGTCAGACTGTTACAAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGACTCCTCATCTATGGTGCATTCACCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGTAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTATATTACTGTCAGCAGTATGGTAGCTCATTCCTCACTTTCGGCGGAGGGACCAAGCTGGAGATCAAA 357 5706 2010DIVMTQTPGTLSLSPGERVTLSCRASQTVTSSYLAWYQQKPGQAPRLLIYGAFTRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSFLTFGG GTKLEIK 357 57072011 RASQTVTSSYLA 357 5708 2012 AGGGCCAGTCAGACTGTTACAAGCAGCTACTTAGCC 3575709 2013 GAFTRAT 357 5710 2014 GGTGCATTCACCAGGGCCACT 357 5711 2015QQYGSSFLT 357 5712 2016 CAGCAGTATGGTAGCTCATTCCTCACT 358 5713 2017GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTAGTAGTAGTAGTTACATATACTACGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATGTGCAATATAGTGGCTACGATTCTGGGTACTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA 358 5714 2018EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDVQYSGYDSGYYFDYWGQGTLVTVSS 358 5715 2019 FTFSSYSMN 358 5716 2020TTCACCTTCAGTAGCTATAGCATGAAC 358 5717 2021 SISSSSSYIYYADSVKG 358 57182022 TCCATTAGTAGTAGTAGTAGTTACATATACTACGCAGACTCAGTGAAG GGC 358 5719 2023ARDVQYSGYDSGYYFDY 358 5720 2024GCGAGAGATGTGCAATATAGTGGCTACGATTCTGGGTACTACTTTGAC TAC 358 5721 2025CAGCCTGTGCTGACTCAGCCACCCTCAGTGTCTGGGGCCCCAGGACAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTCATCTATGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGCCTGAGTGCCCTTTATGTCTTCGGAACTGGGACCAAGGTGACCGTC CTA 358 5722 2026QPVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSAL YVFGTGTKVTVL 358 57232027 TGSSSNIGAGYDVH 358 5724 2028ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC 358 5725 2029 GNSNRPS 3585726 2030 GGTAACAGCAATCGGCCCTCA 358 5727 2031 QSYDSSLSALYV 358 5728 2032CAGTCCTATGACAGCAGCCTGAGTGCCCTTTATGTC 359 5729 2033GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCGGGGGGGTCCCTGAGACTCTCCTGTGCAGGCTCTGGATTCGCCTTCGGTAGCTTCGCGATGCACTGGGTCCGTCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCTGTTATTTCATTTGACGGAAAGAATACAAAATATGCTGACTCCGTGAAGGGCCGATTCACCACCTCCAGAGACAATTCCAGGAACACGCTCTATCTCCAAATGGACAGCCTGAGAGGTGACGACACGGCTATATATTACTGCGCGACAATTAGGGGAATTGTGGCTGGCCTTTGTGACAACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 359 5730 2034EVQLVESGGGVVQPGGSLRLSCAGSGFAFGSFAMHWVRQAPGKGLEWVAVISFDGKNTKYADSVKGRFTTSRDNSRNTLYLQMDSLRGDDTAIYYCATIRGIVAGLCDNWGQGTLVTVSS 359 5731 2035 FAFGSFAMH 359 5732 2036TTCGCCTTCGGTAGCTTCGCGATGCAC 359 5733 2037 VISFDGKNTKYADSVKG 359 57342038 GTTATTTCATTTGACGGAAAGAATACAAAATATGCTGACTCCGTGAA GGGC 359 5735 2039ATIRGIVAGLCDN 359 5736 2040 GCGACAATTAGGGGAATTGTGGCTGGCCTTTGTGACAAC 3595737 2041 CAGCCTGTGCTGACTCAATCATCGTCTGACTCTGCTTCCCTGGGAGCCTCGGTCAAGCTCACCTGTACTCTGAGCAGTGGCCACAGAAACTACATCATCGCATGGCATCAACAACAACCAGGGAAGGCCCCTCGGTTCCTGATGAAGGTTGAAGGTAGTGGAAGCTTCACCATGGGGAGCGGAGTTCCTGATCGCTTCTCGGGCTCCAGCTCTGGGGCTGACCGCTACCTCACCATCTCCAACCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGAGGCCTGGGACTTTAACACGGGGGGGGTCTTCGGCGGAGGCACCCAGCTGACCGT CCTC 359 5738 2042QPVLTQSSSDSASLGASVKLTCTLSSGHRNYIIAWHQQQPGKAPRFLMKVEGSGSFTMGSGVPDRFSGSSSGADRYLTISNLQSEDEADYYCEAWDFNT GGVFGGGTQLTVL 359 57392043 TLSSGHRNYIIA 359 5740 2044 ACTCTGAGCAGTGGCCACAGAAACTACATCATCGCA 3595741 2045 VEGSGSFTMGS 359 5742 2046 GTTGAAGGTAGTGGAAGCTTCACCATGGGGAGC359 5743 2047 EAWDFNTGGV 359 5744 2048 GAGGCCTGGGACTTTAACACGGGGGGGGTC360 5745 2049 GAGGTGCAGCTGGTGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGACCCTGTCCCTCACCTGCGCTGTCTCTGGTGACTCCATCGTCGGTAGTGACTGGTGGAGTTGGATCCGCCAGCCCCCCGGGAAGGGGCTGGAGTGGATTGGAGATATCTATCATGGTGGGACCACCAGCTACAACCCGTCCCTTAAGAGTCGAGTCACCATGTCAGTAGACAAGTCCAAGAACCAATTCTCCCTGAAGCTGACCTCTGTCACCGCCGCGGACACAGCCGTGTATTACTGTGCGAGACTCTCGGGAAATTGTAGTGGTGGTAGCTGTTACTCGCCCTTTGACCACTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCA 360 5746 2050EVQLVESGPGLVKPSGTLSLTCAVSGDSIVGSDWWSWIRQPPGKGLEWIGDIYHGGTTSYNPSLKSRVTMSVDKSKNQFSLKLTSVTAADTAVYYCARLSGNCSGGSCYSPFDHWGQGTLVTVSS 360 5747 2051 DSIVGSDWWS 360 5748 2052GACTCCATCGTCGGTAGTGACTGGTGGAGT 360 5749 2053 DIYHGGTTSYNPSLKS 360 57502054 GATATCTATCATGGTGGGACCACCAGCTACAACCCGTCCCTTAAGAGT 360 5751 2055ARLSGNCSGGSCYSPFDH 360 5752 2056GCGAGACTCTCGGGAAATTGTAGTGGTGGTAGCTGTTACTCGCCCTTT GACCAC 360 5753 2057GACATCCAGATGACCCAGTCTCCATCCTCCTTGTCTGCATCTGTGGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGACCATTAATGGTTATTTAAATTGGTATCAACAAAGACCAGGGAAAGCCCCTAAACTCCTGATCTCTGCTGCATCCAGTTTGCAGAGTGGGGTCCCATCAAGGTTCCGTGGCAGTGGATATGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTATTTCTGTCAACAGAGTTACAATACTGTGTACACTTTTGGGCAGGGGACCAAAGTGGATATCAAA 360 5754 2058DIQMTQSPSSLSASVGDRVTITCRASQTINGYLNWYQQRPGKAPKLLISAASSLQSGVPSRFRGSGYGTDFTLTISSLQPEDFATYFCQQSYNTVYTFGQG TKVDIK 360 5755 2059RASQTINGYLN 360 5756 2060 CGGGCAAGTCAGACCATTAATGGTTATTTAAAT 360 57572061 AASSLQS 360 5758 2062 GCTGCATCCAGTTTGCAGAGT 360 5759 2063 QQSYNTVYT360 5760 2064 CAACAGAGTTACAATACTGTGTACACT 361 5761 2065CAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTAGCAGCTACTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGGGATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCGCTCCAAGGCCAGGTCACCATCTCAGGCGACAAGTCCATCAGTACCGCCTTCCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATTACTGTGCGAGACCCATGACTACCCAAGAAGGTTTTGATTTGTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA 361 5762 2066QVQLVQSGAEVKKPGESLKISCKGSGYSFSSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSLQGQVTISGDKSISTAFLQWSSLKASDTAMYYCARP MTTQEGFDLWGQGTMVTVSS361 5763 2067 YSFSSYWIG 361 5764 2068 TACAGCTTTAGCAGCTACTGGATCGGC 3615765 2069 IIYPGDSDTRYSPSLQG 361 5766 2070ATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCGCTCCAA GGC 361 5767 2071ARPMTTQEGFDL 361 5768 2072 GCGAGACCCATGACTACCCAAGAAGGTTTTGATTTG 361 57692073 GACATCCGGTTGACCCAGTCTCCATCTTCTGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCGACTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACTATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGACTAACAGTTTCCTCCCGCTCACTTTCGGCGGAGGGACCAAAGTGGATATCAAA 361 5770 2074DIRLTQSPSSVSASVGDRVTITCRASQGISDWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTNSFLPLTFGG GTKVDIK 361 57712075 RASQGISDWLA 361 5772 2076 CGGGCGAGTCAGGGTATTAGCGACTGGTTAGCC 3615773 2077 AASSLQS 361 5774 2078 GCTGCATCCAGTTTGCAAAGT 361 5775 2079QQTNSFLPLT 361 5776 2080 CAACAGACTAACAGTTTCCTCCCGCTCACT 362 5777 2081GAGGTGCAGCTGGTGGAGTCGGGCCCCCGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACCGTCTATGGTGGCTCCATCAGCGGTGGTCAAAACTACTACAGTTGGGTCCGCCAGCCCCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTTTTCCAGTGGGACCACCTACTACAAGCCGTCCCTCAAGAGTCGAATTTCCATTTCATTTGACACGTCCAAGAACCAGTTCTCCCTGAACCTGGCCTCTGTGACGGCCGCAGACACGGCCGTATATTTCTGTGCCAGATCCGCTGACATTGATATCGTTTGGGGGAGTTCTCTCTACATGCCTCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 362 5778 2082EVQLVESGPRLVKPSQTLSLTCTVYGGSISGGQNYYSWVRQPPGKGLEWIGYIFSSGTTYYKPSLKSRISISFDTSKNQFSLNLASVTAADTAVYFCARSADIDIVWGSSLYMPLWGQGTLVTVSS 362 5779 2083 GSISGGQNYYS 362 5780 2084GGCTCCATCAGCGGTGGTCAAAACTACTACAGT 362 5781 2085 YIFSSGTTYYKPSLKS 3625782 2086 TACATCTTTTCCAGTGGGACCACCTACTACAAGCCGTCCCTCAAGAGT 362 5783 2087ARSADIDIVWGSSLYMPL 362 5784 2088GCCAGATCCGCTGACATTGATATCGTTTGGGGGAGTTCTCTCTACATG CCTCTC 362 5785 2089GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGACAAAGAGCCACCCTCTCCTGCAGGGCCACTCACATTGTCAGTAACAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCCATGGTGTTTCCATCAGGGCCACTGGCATCCCAGACAGGTTCTCTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTTCTGTCAGCAGTATGGTACCTCACCGTGGACGTTCGGCCAAGGGACCAAGCTGGAGATCAAA 362 5786 2090EIVLTQSPGTLSLSPGQRATLSCRATHIVSNSYLAWYQQKPGQAPRLLIHGVSIRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYFCQQYGTSPWTFGQG TKLEIK 362 5787 2091RATHIVSNSYLA 362 5788 2092 AGGGCCACTCACATTGTCAGTAACAGCTACTTAGCC 362 57892093 GVSIRAT 362 5790 2094 GGTGTTTCCATCAGGGCCACT 362 5791 2095 QQYGTSPWT362 5792 2096 CAGCAGTATGGTACCTCACCGTGGACG 363 5793 2097CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCGGGGGGGTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTTACCTTCAGCAGTTATGCCATGAATTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGACTGGGTCTCCTCTATCAGTGCTGGTAGCAATTTCATAGACGACGCAGACTCAGTGAAGGGCCGCTTCACCATCTCCAGAGACAACGCCAGGAACTCACTGTTTCTGCAGATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAATTGGGTACAGTAGCGCGCACCACTACCAGTACTACATGGACGTCTGGGGCACGGGGACCACGGTCACCGTCTCCTCA 363 5794 2098QVQLVESGGGLVKPGGSLRLSCVASGFTFSSYAMNWVRQAPGKGLDWVSSISAGSNFIDDADSVKGRFTISRDNARNSLFLQMNSLRAEDTAVYYCARIGYSSAHHYQYYMDVWGTGTTVTVSS 363 5795 2099 FTFSSYAMN 363 5796 2100TTTACCTTCAGCAGTTATGCCATGAAT 363 5797 2101 SISAGSNFIDDADSVKG 363 57982102 TCTATCAGTGCTGGTAGCAATTTCATAGACGACGCAGACTCAGTGAA GGGC 363 5799 2103ARIGYSSAHHYQYYMDV 363 5800 2104GCGAGAATTGGGTACAGTAGCGCGCACCACTACCAGTACTACATGGA CGTC 363 5801 2105CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGCAGCAGCTCCAACATCGGGGCAGGTTATGATGTCCACTGGTACCAGGATCTTCCAGGAACTGCCCCCAAACTCCTCATCTATGGTAACACCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCGCCTCAGCCTCCCTGGTCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAAGAGCCTGAGTGGTGGGTATGTCTTCGGAACTGGGACCAAGGTCACCGT CCTA 363 5802 2106QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQDLPGTAPKLLIYGNTNRPSGVPDRFSGSKSGASASLVITGLQAEDEADYYCQSYDKSLSG GYVFGTGTKVTVL 363 58032107 TGSSSNIGAGYDVH 363 5804 2108ACTGGCAGCAGCTCCAACATCGGGGCAGGTTATGATGTCCAC 363 5805 2109 GNTNRPS 3635806 2110 GGTAACACCAATCGGCCCTCA 363 5807 2111 QSYDKSLSGGYV 363 5808 2112CAGTCCTATGACAAGAGCCTGAGTGGTGGGTATGTC 364 5809 2113CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAGGGTCACCTGCAAGGCCTCTGGATACACCTTCACCGACTACTTTATGAACTGGGTGCGACAGGCCCCTGGAGGGGGCCTTGAGTGGATGGGGTGGATCAATCCTCTCAGTGGAGTCACAAAATATGCACAGCAGTTTCAGGGCAGTGTCACCATGACCACTGACACGTCCATCACCACAGGCTACATGGAGCTGAGGAGCCTGAGAGTTGACGACACGGCCGTCTATTATTGTGCGAGCCAGTCTTCCCCTTACACCCCGGGCGCCATGGGCGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTTCA 364 5810 2114QVQLVQSGAEVKKPGASVRVTCKASGYTFTDYFMNWVRQAPGGGLEWMGWINPLSGVTKYAQQFQGSVTMTTDTSITTGYMELRSLRVDDTAVYYCASQSSPYTPGAMGVWGQGTTVTVSS 364 5811 2115 YTFTDYFMN 364 5812 2116TACACCTTCACCGACTACTTTATGAAC 364 5813 2117 WINPLSGVTKYAQQFQG 364 58142118 TGGATCAATCCTCTCAGTGGAGTCACAAAATATGCACAGCAGTTTCA GGGC 364 5815 2119ASQSSPYTPGAMGV 364 5816 2120 GCGAGCCAGTCTTCCCCTTACACCCCGGGCGCCATGGGCGTC364 5817 2121 TCCTATGAGCTGATACAGCTACCCTCGGTGTCAGTGTCCCCAGGACAGACGGCCAGGATCACCTGCTCTGGAGATGCATTGCCAAAGCAATATGCTTATTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGCTGGTGATATATAAAGACAGTGAGAGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAGCTCAGGGACAACAGTCACGTTGACCATCAGTGGAGTCCAGGCAGAAGACGAGGCTGACTATTACTGTCAATCAGCAGACAGCAGTGGTACTTATCCGGTGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 364 5818 2122SYELIQLPSVSVSPGQTARITCSGDALPKQYAYWYQQKPGQAPVLVIYKDSERPSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCQSADSSGTYPVVFG GGTKLTVL 364 58192123 SGDALPKQYAY 364 5820 2124 TCTGGAGATGCATTGCCAAAGCAATATGCTTAT 3645821 2125 KDSERPS 364 5822 2126 AAAGACAGTGAGAGGCCCTCA 364 5823 2127QSADSSGTYPVV 364 5824 2128 CAATCAGCAGACAGCAGTGGTACTTATCCGGTGGTG 365 58252129 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG (ADI-GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA 31382)TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTAGTAGTAGTAATTACATAAACTACGCAGACTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGATTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5826 2130EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWVSSISSSSNYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCARDLLPVERGPAFDIWGQGTMVTVSS 5827 2131 FSFRSYSMN 5828 2132 SISSSSNYINYADSVKG5829 2133 ARDLLPVERGPAFDI 5830 2134TCCTACGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACTATCTCCTGCACTGGGAGCAGCTCCAACATCGGGAGGGGTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCATCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTTCGGTATTCGGCGGAGGGACCAAGGTGACCGTCCT A 5831 2135SYELTQPPSVSGAPGQRVTISCTGSSSNIGRGYDVHWFQQLPGAAPKLLIYANSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGSV FGGGTKVTVL 5832 2136TGSSSNIGRGYDVH 5833 2137 ANSNRPS 5834 2138 QSYDSRLGGSV 366 5835 2139GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG (ADI-GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA 31383)TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTAGTAGTAGTAATTACATAAACTACGCAGACTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGATTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5836 2140EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWVSSISSSSNYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCARDLLPVERGPAFDIWGQGTMVTVSS 5837 2141 FSFRSYSMN 5838 2142 SISSSSNYINYADSVKG5839 2143 ARDLLPVERGPAFDI 5840 2144TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCATCTATCGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTTCGAATTTCGGCGGAGGGACCAAGGTGACCGTCCT A 5841 2145SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQQLPGAAPKLLIYRNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGS NFGGGTKVTVL 5842 2146TGSSSNIGAGYDVH 5843 2147 RNSNRPS 5844 2148 QSYDSRLGGSN 367 5845 2149GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG (ADI-GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA 31384)TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTGCTAGTAGTAATTACATAAACTACGCAGACTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGATTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5846 2150EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWVSSISASSNYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCARDLLPVERGPAFDIWGQGTMVTVSS 5847 2151 FSFRSYSMN 5848 2152 SISASSNYINYADSVKG5849 2153 ARDLLPVERGPAFDI 5850 2154TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCATCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTTCGGTATTCGGCGGAGGGACCAAGGTGACCGTCCT A 5851 2155SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQQLPGAAPKLLIYANSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGS VFGGGTKVTVL 5852 2156TGSSSNIGAGYDVH 5853 2157 ANSNRPS 5854 2158 QSYDSRLGGSV 368 5855 2159GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG (ADI-GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA 31385)TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTAGTAGTAGTACTTACATAAACTACGCAGACTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGATTTGAGTCCCGTCGAGCGGGGTCCCGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5856 2160EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWVSSISSSSTYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCARDLSPVERGPAFDIWGQGTMVTVSS 5857 2161 FSFRSYSMN 5858 2162 SISSSSTYINYADSVKG5859 2163 ARDLSPVERGPAFDI 5860 2164TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCATCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTTCGGTATTCGGCGGAGGGACCAAGGTGACCGTCCT A 5861 2165SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQQLPGAAPKLLIYANSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGS VFGGGTKVTVL 5862 2166TGSSSNIGAGYDVH 5863 2167 ANSNRPS 5864 2168 QSYDSRLGGSV 369 5865 2169GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG (ADI-GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA 31345)TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTGCTAGTAGTAATTACATAAACTACGCAGACTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGATTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5866 2170EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWVSSISASSNYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCARDLLPVERGPAFDIWGQGTMVTVSS 5867 2171 FSFRSYSMN 5868 2172 SISASSNYINYADSVKG5869 2173 ARDLLPVERGPAFDI 5870 2174TCCTACGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACTATCTCCTGCACTGGGAGCAGCTCCAACATCGGGAGGGGTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCATCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTTCGGTATTCGGCGGAGGGACCAAGGTGACCGTCCT A 5871 2175SYELTQPPSVSGAPGQRVTISCTGSSSNIGRGYDVHWFQQLPGAAPKLLIYANSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGSV FGGGTKVTVL 5872 2176TGSSSNIGRGYDVH 5873 2177 ANSNRPS 5874 2178 QSYDSRLGGSV 370 5875 2179GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG (ADI-GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA 31346)TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTGCTAGTAGTAATTACATAAACTACGCAGACTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGATTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5876 2180EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWVSSISASSNYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCARDLLPVERGPAFDIWGQGTMVTVSS 5877 2181 FSFRSYSMN 5878 2182 SISASSNYINYADSVKG5879 2183 ARDLLPVERGPAFDI 5880 2184TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCATCTATCGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTTCGAATTTCGGCGGAGGGACCAAGGTGACCGTCCT A 5881 2185SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQQLPGAAPKLLIYRNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGS NFGGGTKVTVL 5882 2186TGSSSNIGAGYDVH 5883 2187 RNSNRPS 5884 2188 QSYDSRLGGSN 371 5885 2189GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG (ADI-GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA 31354)TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTAGTAGTAGTACTTACATAAACTACGCAGACTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGATTTGAGTCCCGTCGAGCGGGGTCCCGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5886 2190EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWVSSISSSSTYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCARDLSPVERGPAFDIWGQGTMVTVSS 5887 2191 FSFRSYSMN 5888 2192 SISSSSTYINYADSVKG5889 2193 ARDLSPVERGPAFDI 5890 2194TCCTACGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACTATCTCCTGCACTGGGAGCAGCTCCAACATCGGGAGGGGTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCATCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTTCGGTATTCGGCGGAGGGACCAAGGTGACCGTCCT A 5891 2195SYELTQPPSVSGAPGQRVTISCTGSSSNIGRGYDVHWFQQLPGAAPKLLIYANSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGSV FGGGTKVTVL 5892 2196TGSSSNIGRGYDVH 5893 2197 ANSNRPS 5894 2198 QSYDSRLGGSV 372 5895 2199GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG (ADI-GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA 31362)TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTAGTAGTAGTACTTACATAAACTACGCAGACTCAGTGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTACTGTGCGAGAGATTTGAGTCCCGTCGAGCGGGGTCCCGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA 5896 2200EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWVSSISSSSTYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCARDLSPVERGPAFDIWGQGTMVTVSS 5897 2201 FSFRSYSMN 5898 2202 SISSSSTYINYADSVKG5899 2203 ARDLSPVERGPAFDI 5900 2204TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAACTCCTCATCTATCGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGACTGGGTGGTTCGAATTTCGGCGGAGGGACCAAGGTGACCGTCCT A 5901 2205SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQQLPGAAPKLLIYRNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGS NFGGGTKVTVL 5902 2206TGSSSNIGAGYDVH 5903 2207 RNSNRPS 5904 2208 QSYDSRLGGSN

Additional Embodiments

Embodiment 1. An isolated antibody or an antigen-binding fragmentthereof that specifically binds to Respiratory Syncytial Virus (RSV) Fprotein (F), wherein at least one of the CDRH1, a CDRH2, a CDRH3, aCDRL1, a CDRL2, and CDRL3 amino acid sequence of the antibody or theantigen-binding fragment thereof is at least 70% o identical; at least7500 identical; 80% o identical; at least 8500 identical; at least 90% oidentical; at least 9500 identical; at least 96% o identical; at least970% identical; at least 98% o identical; at least 990%; and/or allpercentages of identity in between; to at least one the CDRH1, a CDRH2,a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences asdisclosed in Table 6 of an antibody selected from Antibody Number 232through Antibody Number 372 as disclosed in Table 6; and wherein saidantibody or the antigen-binding fragment thereof also has one or more ofthe following characteristics:

a) the antibody or antigen-binding fragment thereof cross-competes withsaid antibody ar antigen-binding fragment thereof for binding to RSV-F;

b) the antibody or antigen-binding fragment thereof displays betterbinding affinity for the PreF form of RSV-F relative to the PostF form;

c) the antibody or antigen-binding fragment thereof displays a clean orlow polyreactivity profile;

d) the antibody or antigen-binding fragment thereof displaysneutralization activity toward RSV subtype A and RSV subtype B in vitro;

e) the antibody or antigen-binding fragment thereof displays antigenicsite specificity for RSV-F at Site Ø, Site I, Site II, Site III, SiteIV, or Site V;

f) the antibody or antigen-binding fragment thereof displays antigenicsite specificity for RSV-F Site Ø, Site V, or Site III relative to RSV-FSite I, Site II, or Site IV;

g) at least a portion of the epitope with which the antibody orantigen-binding fragment thereof interacts comprises the α3 helix andβ3/β4 hairpin of PreF;

h) the antibody or antigen-binding fragment thereof displays an in vitroneutralization potency (IC₅₀) of between about 0.5 microgram/milliliter(ug/ml) to about 5 ug/ml; between about 0.05 ug/ml to about 0.5 ug/ml;or less than about 0.05 mg/ml;

i) the binding affinity and/or epitopic specificity of the antibody orantigen-binding fragment thereof for any one of the RSV-F variantsdesignated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced oreliminated relative to the binding affinity and/or epitopic specificityof said antibody or antigen-binding fragment thereof for the RSV-F orRSV-F DS-Cav1;

j) the antibody or antigen-binding fragment thereof of displays across-neutralization potency (IC₅₀) against human metapneumovirus(HMPV);

k) the antibody or antigen-binding fragment thereof does not completewith D25, MPE8, palivisumab, motavizumab, or AM-14; or

l) the antibody or antigen-binding fragment thereof displays at leastabout 2-fold; at least about 3-fold; at least about 4-fold; at leastabout 5-fold; at least about 6-fold; at least about 7-fold; at leastabout 8-fold; at least about 9-fold; at least about 10-fold; at leastabout 15-fold; at least about 20-fold; at least about 25-fold; at leastabout 30-fold; at least about 35-fold; at least about 40-fold; at leastabout 50-fold; at least about 55-fold; at least about 60-fold; at leastabout 70-fold; at least about 80-fold; at least about 90-fold; at leastabout 100-fold; greater than about 100-fold; and folds in between any ofthe foregoing; greater neutralization potency (IC50) than D25 and/orpalivizumab.

Embodiment 2. The isolated antibody or antigen-binding fragment thereofof Embodiment 1, wherein the antibody or antigen-binding fragmentthereof comprises: at least two; at least three; at least 4; at least 5;at least 6; at least 7; at least 8; at least 9; at least 10; at least11; or at least 12; of characteristics a) through 1).

Embodiment 3. The isolated antibody or antigen-binding fragment thereofof Embodiment 1 or 2, wherein the antibody or antigen-binding fragmentthereof comprises:

a) the CDRH3 amino acid sequence of any one of the antibodies designatedAntibody Number 232 through Antibody Number 372 as disclosed in Table 6;

b) the CDRH2 amino acid sequence of any one of the antibodies designatedAntibody Number 232 through Antibody Number 372 as disclosed in Table 6;

c) the CDRH1 amino acid sequence of any one of the antibodies designatedAntibody Number 232 through Antibody Number 372 as disclosed in Table 6;

d) the CDRL3 amino acid sequence of any one of the antibodies designatedAntibody Number 232 through Antibody Number 372 as disclosed in Table 6;

e) the CDRL2 amino acid sequence of any one of the antibodies designatedAntibody Number 232 through Antibody Number 372 as disclosed in Table 6;

f) the CDRL1 amino acid sequence of any one of the antibodies designatedAntibody Number 232 through Antibody Number 372 as disclosed in Table 6;or

g) any combination of two or more of a), b), c), d), e), and f).

Embodiment 4. The isolated antibody or antigen-binding fragment thereofof any one of Embodiments 1 through 3, wherein the antibody orantigen-binding fragment thereof comprises:

a) a heavy chain (HC) amino acid sequence of any one of the antibodiesdesignated Antibody Number 232 through Antibody Number 372 as disclosedin Table 6; and/or

b) a light chain (LC) amino acid sequence of any one of the antibodiesdesignated Antibody Number 232 through Antibody Number 372 as disclosedin Table 6.

Embodiment 5. The isolated antibody or antigen-binding fragment thereofof any one of Embodiments 1 through 4, wherein the antibody is selectedfrom the group consisting antibodies that are at least 70% identical; atleast 75% identical; 80% identical; at least 85% identical; at least 90%identical; at least 95% identical; at least 96% identical; at least 97%identical; at least 98% identical; at least 99%; and/or all percentagesof identity in between; to any one of the antibodies designated asAntibody Number 232 through Antibody Number 372 as disclosed in Table 6.

Embodiment 6. The isolated antibody or antigen-binding fragment thereofof any one of Embodiments 1 through 5, wherein the antibody is selectedfrom the group consisting of the antibodies designated as Antibody 232through Antibody Number 372 as disclosed in Table 6.

Embodiment 7. An isolated nucleic acid sequence encoding an antibody orantigen-binding fragment thereof according to any one of Embodiments 1through 6.

Embodiment 8. An expression vector comprising the isolated nucleic acidsequence according to Embodiment 7.

Embodiment 9. A host cell transfected, transformed, or transduced withthe nucleic acid sequence according to Embodiment 7 or the expressionvector according to Embodiment 8.

Embodiment 10. A pharmaceutical composition comprising: one or more ofthe isolated antibodies or antigen-binding fragments thereof accordingto any one of Embodiments 1 through 6; and a pharmaceutically acceptablecarrier and/or excipient.

Embodiment 11. A pharmaceutical composition comprising: one or morenucleic acid sequences according to Embodiment 7; or one or more theexpression vectors according to Embodiment 8; and a pharmaceuticallyacceptable carrier and/or excipient.

Embodiment 12. A transgenic organism comprising the nucleic acidsequence according to Embodiment 7; or the expression vector accordingto Embodiment 8.

Embodiment 13. A method of treating or preventing a RespiratorySyncytial Virus (RSV) infection, ar at least one symptom associated withRSV infection, comprising administering to a patient in need thereof orsuspected of being in need thereof:

a) one or more antibodies or antigen-binding fragments thereof accordingto any of Embodiments 1 through 6;

b) a nucleic acid sequences according to Embodiment 7;

c) an expression vector according to Embodiment 8;

d) a host cell according to Embodiment 9; or

e) a pharmaceutical composition according Embodiment 10 or Embodiment11; such that the RSV infection is treated or prevented, or the at leaston symptom associated with RSV infection is treated, alleviated, orreduced in severity.

Embodiment 14. A method of treating or preventing either a RespiratorySyncytial Virus (RSV) infection or a human metapneumovirus (HMPV)infection, ar at least one symptom associated with said RSV infection orsaid HMPV infection, comprising administering to a patient in needthereof or suspected of being in need thereof:

a) one or more antibodies or antigen-binding fragments thereof accordingto any of Embodiments 1 through 6;

b) a nucleic acid sequences according to Embodiment 7;

c) an expression vector according to Embodiment 8;

d) a host cell according to Embodiment 9; or

e) a pharmaceutical composition according Embodiment 10 or Embodiment11; such that the RSV infection is treated or prevented, or the at leaston symptom associated with RSV infection is treated, alleviated, orreduced in severity.

Embodiment 15. The method according to Embodiment 14, wherein the one ormore antibodies or antigen-binding fragments thereof comprises AntibodyNumber 340.

Embodiment 16. The method according to any one of Embodiments 13 through15, wherein the method further comprises administering to the patient asecond therapeutic agent.

Embodiment 17. The method according to Embodiment 16, wherein the secondtherapeutic agent is selected group consisting of: an antiviral agent; avaccine specific for RSV, a vaccine specific for

influenza virus, or a vaccine specific for metapneumovirus (MPV); ansiRNA specific for an RSV antigen or a metapneumovirus (MPV) antigen; asecond antibody specific for an RSV antigen or a metapneumovirus (MPV)antigen; an anti-IL4R antibody, an antibody specific for an influenzavirus antigen, an anti-RSV-G antibody and a NSAID.

Embodiment 18. A pharmaceutical composition comprising any one or moreof the isolated antibodies or antigen-binding fragments thereof of anyone of Embodiments 1 through 7 and a pharmaceutically acceptable carrierand/or excipient.

Embodiment 19. The pharmaceutical composition according to Embodiment 18for use in preventing a respiratory syncytial virus (RSV) infection in apatient in need thereof or suspected of being in need thereof, or fortreating a patient suffering from an RSV infection, or for amelioratingat least one symptom or complication associated with the infection,wherein the infection is either prevented, or at least one symptom orcomplication associated with the infection is prevented, ameliorated, orlessened in severity and/or duration as a result of such use.

Embodiment 20. The pharmaceutical composition according to Embodiment 18for us in treating or preventing either a Respiratory Syncytial Virus(RSV) infection or a human metapneumovirus (HMPV) infection, or at leastone symptom associated with said RSV infection or said HMPV infection,in a patient in need thereof or suspected of being in need thereof,wherein the infection is either prevented, or at least one symptom orcomplication associated with the infection is prevented, ameliorated, orlessened in severity and/or duration as a result of such use.

Embodiment 21. Use of the pharmaceutical composition of Embodiment 18 inthe manufacture of a medicament for preventing a respiratory syncytialvirus (RSV) infection in a patient in need thereof, or for treating apatient suffering from an RSV infection, or for ameliorating at leastone symptom or complication associated with the infection, wherein theinfection is either prevented, or at least one symptom or complicationassociated with the infection is prevented, ameliorated, or lessened inseverity and/or duration.

Embodiment 22. Use of the pharmaceutical composition of Embodiment 18 inthe manufacture of a medicament for preventing either a RespiratorySyncytial Virus (RSV) infection or a human metapneumovirus (HMPV)infection, or at least one symptom associated with said RSV infection orsaid HMPV infection, in a patient in need thereof or suspected of beingin need thereof, wherein the infection is either prevented, or at leastone symptom or complication associated with the infection is prevented,ameliorated, or lessened in severity and/or duration as a result of suchuse.

1-22. (canceled)
 23. An isolated antibody or an antigen-binding fragmentthereof that specifically binds to Respiratory Syncytial Virus (RSV) Fprotein (F), wherein the antibody or antigen-binding fragment thereofcomprises a variable light chain (VL) polypeptide and a variable heavychain (VH) polypeptide comprising the same CDRH1, a CDRH2, a CDRH3, aCDRL1, a CDRL2, and a CDRL3 amino acid sequences as an antibody selectedfrom Antibody Number 232 through Antibody Number 372 as disclosed inTable
 6. 24. The isolated antibody or antigen-binding fragment thereofof claim 23, wherein the antibody or antigen-binding fragment thereofcomprises: at least two; at least three; at least 4; at least 5; atleast 6; at least 7; at least 8; at least 9; at least 10; at least 11;or at least 12; of characteristics a) through 1) set forth below: a) theantibody or antigen-binding fragment thereof cross-competes with saidantibody ar antigen-binding fragment thereof for binding to RSV-F; b)the antibody or antigen-binding fragment thereof displays better bindingaffinity for the PreF form of RSV-F relative to the PostF form; c) theantibody or antigen-binding fragment thereof displays a clean or lowpolyreactivity profile; d) the antibody or antigen-binding fragmentthereof displays neutralization activity toward RSV subtype A and RSVsubtype B in vitro; e) the antibody or antigen-binding fragment thereofdisplays antigenic site specificity for RSV-F at Site Ø, Site I, SiteII, Site III, Site IV, or Site V; f) the antibody or antigen-bindingfragment thereof displays antigenic site specificity for RSV-F Site Ø,Site V, or Site III relative to RSV-F Site I, Site II, or Site IV; g) atleast a portion of the epitope with which the antibody orantigen-binding fragment thereof interacts comprises the α3 helix andβ3/β4 hairpin of PreF; h) the antibody or antigen-binding fragmentthereof displays an in vitro neutralization potency (IC50) of betweenabout 0.5 microgram/milliliter (ug/ml) to about 5 ug/ml; between about0.05 ug/ml to about 0.5 ug/ml; or less than about 0.05 mg/ml; i) thebinding affinity and/or epitopic specificity of the antibody orantigen-binding fragment thereof for any one of the RSV-F variantsdesignated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced oreliminated relative to the binding affinity and/or epitopic specificityof said antibody or antigen-binding fragment thereof for the RSV-F orRSV-F DS-Cav1; j) the antibody or antigen-binding fragment thereof ofdisplays a cross-neutralization potency (IC50) against humanmetapneumovirus (HMPV); k) the antibody or antigen-binding fragmentthereof does not complete with D25, MPE8, palivisumab, motavizumab, orAM-14; or l) the antibody or antigen-binding fragment thereof displaysat least about 2-fold; at least about 3-fold; at least about 4-fold; atleast about 5-fold; at least about 6-fold; at least about 7-fold; atleast about 8-fold; at least about 9-fold; at least about 10-fold; atleast about 15-fold; at least about 20-fold; at least about 25-fold; atleast about 30-fold; at least about 35-fold; at least about 40-fold; atleast about 50-fold; at least about 55-fold; at least about 60-fold; atleast about 70-fold; at least about 80-fold; at least about 90-fold; atleast about 100-fold; greater than about 100-fold; and folds in betweenany of the foregoing; greater neutralization potency (IC50) than D25and/or palivizumab.
 25. The isolated antibody or antigen-bindingfragment thereof of claim 23, wherein the antibody or antigen-bindingfragment thereof comprises a VL polypeptide amino acid sequence and/or aVH polypeptide amino acid sequence according to any one of theantibodies designated Antibody Number 232 through Antibody Number 372 asdisclosed in Table
 6. 26. The isolated antibody or antigen-bindingfragment thereof of claim 25, wherein the antibody or antigen-bindingfragment thereof comprises the same VH and VL polypeptides of any one ofthe antibodies designated Antibody Number 232 through Antibody Number372 in Table
 6. 27. The isolated antibody or antigen-binding fragmentthereof of claim 23, wherein the antibody is selected from AntibodyNumber 232 through Antibody Number 372 as disclosed in Table
 6. 28. Anisolated nucleic acid sequence encoding an antibody or antigen-bindingfragment thereof according to claim
 23. 29. An expression vectorcomprising the isolated nucleic acid sequence according to claim
 28. 30.A host cell transfected, transformed, or transduced with the nucleicacid sequence according to claim 28 or an expression vector comprisingthe nucleic acid sequence.
 31. A pharmaceutical composition comprising:one or more of the isolated antibodies or antigen-binding fragmentsthereof according to claim 23; and a pharmaceutically acceptable carrierand/or excipient.
 32. A method of treating or preventing a RespiratorySyncytial Virus (RSV) infection, or at least one symptom associated withRSV infection, comprising administering to a patient in need thereof orsuspected of being in need thereof: a) one or more antibodies orantigen-binding fragments thereof according to claim 23; b) nucleic acidsequences encoding the one or more antibodies or antigen-bindingfragments of a); c) an expression vector comprising nucleic acidsequences according to b); d) a host cell transfected, transformed, ortransduced with the nucleic acid sequences or vector according to b) orc); or e) a pharmaceutical composition comprising any of a) to d); suchthat the RSV infection is treated or prevented, or the at least onsymptom associated with RSV infection is treated, alleviated, or reducedin severity.
 33. A method of treating or preventing either a RespiratorySyncytial Virus (RSV) infection or a human metapneumovirus (HMPV)infection, or at least one symptom associated with said RSV infection orsaid HMPV infection, comprising administering to a patient in needthereof or suspected of being in need thereof: a) one or more antibodiesor antigen-binding fragments thereof according to claim 23; b) nucleicacid sequences encoding the one or more antibodies or antigen-bindingfragments of a); c) an expression vector comprising nucleic acidsequences according to b); d) a host cell transfected, transformed, ortransduced with the nucleic acid sequences or vector according to b) orc); or e) a pharmaceutical composition comprising any of a) to d); suchthat the RSV infection is treated or prevented, or the at least onsymptom associated with RSV infection is treated, alleviated, or reducedin severity.
 34. The method according to claim 32, wherein the methodfurther comprises administering to the patient a second therapeuticagent.
 35. The method according to claim 34, wherein the secondtherapeutic agent is selected group consisting of: another antiviralagent; a vaccine specific for RSV, a vaccine specific for influenzavirus, or a vaccine specific for metapneumovirus (MPV); an siRNAspecific for an RSV antigen or a metapneumovirus (MPV) antigen; a secondantibody specific for an RSV antigen or a metapneumovirus (MPV) antigen;an anti-IL4R antibody, an antibody specific for an influenza virusantigen, an anti-RSV-G antibody and a NSAID.